Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula II:wherein Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, and R&lt;2&gt;, R&lt;2&#39;&gt;, R&lt;x&gt;, and R&lt;y &gt;are as described in the specification. Ring C has an ortho substituent and is optionally substituted in the non-ortho positions. R&lt;2 &gt;and R&lt;2&#39;&gt; are optionally taken together with their intervening atoms to form a fused ring system, such as an indazole ring; and R&lt;x &gt;and R&lt;y &gt;are optionally taken together with their intervening atoms to form a fused ring system, such as a quinazoline ring. The compounds are useful as protein kinase inhibitors, especially as inhibitors of GSK-3, for treating diseases such as diabetes and Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/232,795 filed Sep. 15, 2000, U.S. Provisional Patent ApplicationNo. 60/257,887 filed Dec. 21, 2000 and U.S. Provisional PatentApplication No. 60/286,949 filed Apr. 27, 2001, the contents of whichare incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is in the field of medicinal chemistry and relatesto compounds that are protein kinase inhibitors, compositions containingsuch compounds and methods of use. More particularly, this inventionrelates to compounds that are inhibitors of GSK-3 and Aurora-2 proteinkinases. The invention also relates to methods of treating diseasesassociated with these protein kinases, such as diabetes, cancer andAlzheimer's disease.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of enzymes and otherbiomolecules associated with target diseases. One important class ofenzymes that has been the subject of extensive study is the proteinkinases.

Protein kinases mediate intracellular signal transduction. They do thisby effecting a phosphoryl extracellular and other stimuli cause avariety of cellular responses to occur inside the cell. Examples of suchstimuli include environmental and chemical stress signals (e.g. osmoticshock, heat shock, ultraviolet radiation, bacterial endotoxin, H₂O₂),cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor α(TNF-α)), and growth factors (e.g. granulocytemacrophage-colony-stimulating factor (GM-CSF), and fibroblast growthfactor (FGF). An extracellular stimulus may effect one or more cellularresponses related to cell growth, migration, differentiation, secretionof hormones, activation of transcription factors, muscle contraction,glucose metabolism, control of protein synthesis and regulation of cellcycle.

Many diseases are associated with abnormal cellular responses triggeredby protein kinase-mediated events. These diseases include autoimmunediseases, inflammatory diseases, neurological and neurodegenerativediseases, cancer, cardiovascular diseases, allergies and asthma,Alzheimer's disease or hormone-related diseases. Accordingly, there hasbeen a substantial effort in medicinal chemistry to find protein kinaseinhibitors that are effective as therapeutic agents.

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is believed to be involved in protein phosphorylation events thatregulate the cell cycle. Specifically, Aurora-2 may play a role incontrolling the accurate segregation of chromosomes during mitosis.Misregulation of the cell cycle can lead to cellular proliferation andother abnormalities. In human colon cancer tissue, the aurora-2 proteinhas been found to be overexpressed. See Bischoff et al., EMBO J., 1998,17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646;Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein where Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al.,Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

As a result of the biological importance of GSK-3, there is currentinterest in therapeutically effective GSK-3 inhbitors. Small moleculesthat inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) andWO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3activity, other protein kinases have also been targeted for treating thesame diseases. However, the various protein kinases often act throughdifferent biological pathways. For example, certain quinazolinederivatives have been reported recently as inhibitors of p38 kinase (WO00/12497 to Scios). The compounds are reported to be useful for treatingconditions characterized by enhanced p38-α activity and/or enhancedTGF-β activity. While p38 activity has been implicated in a wide varietyof diseases, including diabetes, p38 kinase is not reported to be aconstituent of an insulin signaling pathway that regulates glycogensynthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibitionwould not be expected to enhance glycogen synthesis and/or glucoseuptake.

There is a continued need to find new therapeutic agents to treat humandiseases. The protein kinases aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant role in cancer, diabetes, Alzheimer's disease and otherdiseases.

DESCRIPTION OF THE INVENTION

It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of aurora-2 and GSK-3. Thesecompounds have the general formula I:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ to Z⁴ are as described below;

Ring A is selected from the group consisting of:

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R² are independently selected from —R, —T—W—R⁶, or R² and R^(2′)are taken together with their intervening atoms to form a fused, 5-8membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R² is substitutedby R⁴;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(C₁₋₆ aliphatic),—CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the same nitrogen are taken togetherto form a 5-8 membered heterocyclyl or heteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—,—N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R₆, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶) 2, or —CO₂R⁶; and

R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

As used herein, the following definitions shall apply unless otherwiseindicated. The phrase “optionally substituted” is used interchangeablywith the phrase “substituted or unsubstituted” or with the term“(un)substituted.” Unless otherwise indicated, an optionally substitutedgroup may have a substituent at each substitutable position of thegroup, and each substitution is independent of the other.

The term “aliphatic” as used herein means straight-chain, branched orcyclic C₁-C₁₂ hydrocarbons which are completely saturated or whichcontain one or more units of unsaturation but which are not aromatic.For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” asused herein means an aliphatic ring system having three to fourteenmembers. The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” whether saturated or partially unsaturated, also refers torings that are optionally substituted. The terms “carbocycle”,“carbocyclyl”, “carbocyclo”, or “carbocyclic” also include aliphaticrings that are fused to one or more aromatic or nonaromatic rings, suchas in a decahydronaphthyl or tetrahydronaphthyl, where the radical orpoint of attachment is on the aliphatic ring.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinincludes non-aromatic ring systems having five to fourteen members,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom such as N, O, or S.Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromatic ringgroups having five to fourteen members. Examples of heteroaryl ringsinclude 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R^(o), —OR^(o),—SR^(o), 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such asacyloxy), phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph),—CH₂(Ph), substituted —CH₂(Ph), —CH₂CH₂(Ph), substituted —CH₂CH₂(Ph),—NO₂, —CN, —N(R^(o))₂, —NR^(o)C(O)R^(o), —NR^(o)C(O)N(R^(o))₂,—NR^(o)CO₂R^(o), —NR^(o)NR^(o)C(O)R^(o), —NR^(o)NR^(o)C(O)N(R^(o))₂,—NR^(o)NR^(o)CO₂R^(o), —C(O)C(O)R^(o), —C(O)CH₂C(O)R^(o), —CO₂R^(o),—C(O)R^(o), —C(O)N(R^(o))₂, —OC(O)N(R^(o))₂, —S(O)₂R^(o), —SO₂N(R^(o))₂,—S(O)R^(o), —NR^(o)SO₂N(R^(o))₂, —NR^(o)SO₂R^(o), —C(═S)N(R^(o))₂,—C(═NH)—, N(R^(o))₂, —(CH₂)_(y)NHC(O)R^(o),—(CH₂)_(y)NHC(O)CH(V—R^(o))(R^(o)); wherein R^(o) is hydrogen, asubstituted or unsubstituted aliphatic group, an unsubstitutedheteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, —O(Ph),substituted —O(Ph), —CH₂(Ph), or substituted —CH₂(Ph); y is 0-6; and Vis a linker group Examples of substituents on the aliphatic group or thephenyl ring of R^(o) include amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Examples of suitable substituents on the saturatedcarbon of an aliphatic group or of a non-aromatic heterocyclic ringinclude those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: —O, ═S, ═NNHR*, ═NN(R*)₂, ═N—,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R isindependently selected from hydrogen, an unsubstituted aliphatic groupor a substituted aliphatic group. Examples of substituents on thealiphatic group include amino, alkylamino, dialkylamino, aminocarbonyl,halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano,carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, orhaloalkyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclicring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—, N(R⁺)₂, and —NR⁺SO₂R⁺;wherein R⁺ is hydrogen, an aliphatic group, a substituted aliphaticgroup, phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), CH₂(Ph),substituted CH₂(Ph), or an unsubstituted heteroaryl or heterocyclicring. Examples of substituents on the aliphatic group or the phenyl ringinclude amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly GSK-3, in a biological sample or in a patient. Inanother embodiment, compounds of this invention and pharmaceuticalcompositions thereof, which comprise an amount of the protein kinaseinhibitor effective to treat or prevent a GSK-3-mediated condition and apharmaceutically acceptable carrier, adjuvant, or vehicle, may beformulated for administration to a patient.

The term “GSK-3-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition or state in which GSK-3 isknown to play a role. Such diseases or conditions include, withoutlimitation, diabetes, Alzheimer's disease, Huntington's Disease,Parkinson's Disease, AIDS-associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycetehypertrophy, reperfusion/ischemia, and baldness.

One aspect of this invention relates to a method of enhancing glycogensynthesis and/or lowering blood levels of glucose in a patient in needthereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

Another aspect of the invention relates to inhibiting GSK-3 activity ina biological sample, which method comprises contacting the biologicalsample with a GSK-3 inhibitor of formula I.

Another aspect of this invention relates to a method of inhibitingAurora-2 activity in a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

The term “Aurora-2-mediated condition” or “disease”, as used herein,means any disease or other deleterious condition in which Aurora isknown to play a role. The term “Aurora-2-mediated condition” or“disease” also means those diseases or conditions that are alleviated bytreatment with an Aurora-2 inhibitor. Such conditions include, withoutlimitation, cancer. The term “cancer” includes, but is not limited tothe following cancers: colon and ovarian.

Another aspect of the invention relates to inhibiting Aurora-2 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 inhibitor of formula I, or a compositionthereof.

Another aspect of this invention relates to a method of treating orpreventing a CDK-2-mediated diseases with a CDK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The term “CDK-2-mediated condition” or “disease”, as used herein, meansany disease or other deleterious condition in which CDK-2 is known toplay a role. The term “CDK-2-mediated condition” or “disease” also meansthose diseases or conditions that are alleviated by treatment with aCDK-2 inhibitor. Such conditions include, without limitation, cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis. See Fischer, P. M. andLane, D. P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, S.,Wang, C., Wu, K., Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs,9, 1849 (2000); Fry, D. W. and Garrett, M. D., Current opinion inOncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000).

Another aspect of the invention relates to inhibiting CDK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The term “ERK-mediated condition”, as used herein means any diseasestate or other deleterious condition in which ERK is known to play arole. The term “ERK-2-mediated condition” or “disease” also means thosediseases or conditions that are alleviated by treatment with a ERK-2inhibitor. Such conditions include, without limitation, cancer, stroke,diabetes, hepatomegaly, cardiovascular disease including cardiomegaly,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, atherosclerosis, restenosis, psoriasis, allergic disordersincluding asthma, inflammation, neurological disorders andhormone-related diseases. The term “cancer” includes, but is not limitedto the following cancers: breast, ovary, cervix, prostate, testis,genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma,stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cellcarcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon,adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx,small intestine, colon-rectum, large intestine, rectum, brain andcentral nervous system, and leukemia. ERK-2 protein kinase and itsimplication in various diseases has been described [Bokemeyer et al.1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651;Crews et al., 1992, Science 258, 478; Bjorbaek et al., 1995, J. Biol.Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al.,1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc.Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science 260, 1658; Freyand Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin.Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol.16, 589].

Another aspect of the invention relates to inhibiting ERK-2 activity ina biological sample or a patient, which method comprises administeringto the patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing an AKT-mediated diseases with an AKT inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The term “AKT-mediated condition”, as used herein, means any diseasestate or other deleterious condition in which AKT is known to play arole. The term “AKT-mediated condition” or “disease” also means thosediseases or conditions that are alleviated by treatment with a AKTinhibitor. AKT-mediated diseases or conditions include, but are notlimited to, proliferative disorders, cancer, and neurodegenerativedisorders. The association of AKT, also known as protein kinase B, withvarious diseases has been described [Khwaja, A., Nature, pp. 33-34,1990; Zang, Q. Y., et al, Oncogene, 19 2000; Kazuhiko, N., et al, TheJournal of Neuroscience, 20 2000].

Another aspect of the invention relates to inhibiting AKT activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

Another aspect of this invention relates to a method of treating orpreventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

The term “Src-mediated condition”, as used herein means any diseasestate or other deleterious condition in which Src is known to play arole. The term “Src-mediated condition” or “disease”, also means thosediseases or conditions that are alleviated by treatment with a Srcinhibitor. Such conditions include, without limitation, hypercalcemia,osteoporosis, osteoarthritis, cancer, symptomatic treatment of bonemetastasis, and Paget's disease. Src protein kinase and its implicationin various diseases has been described [Soriano, Cell, 69, 551 (1992);Soriano et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104,137 (1999); Boschelli, Drugs of the Future 2000, 25(7), 717, (2000);Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys. Res.243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (1986); Bolen, Proc.Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257(1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7,1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, CellGrowth Diff., 8, 269 (1997)].

Another aspect of the invention relates to inhibiting Src activity in abiological sample or a patient, which method comprises administering tothe patient a compound of formula I or a composition comprising saidcompound.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

The term “patient” includes human and veterinary subjects.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

The amount effective to inhibit protein kinase, for example, GSK-3 andAurora-2, is one that measurably inhibits the kinase activity wherecompared to the activity of the enzyme in the absence of an inhibitor.Any method may be used to determine inhibition, such as, for example,the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, without limitation, esters, amino acid esters, phosphateesters, metal salts and sulfonate esters.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternization ofany basic nitrogen-containing groups of the compounds disclosed herein.Water or oil-soluble or dispersible products may be obtained by suchquaternization.

The amount of the protein kinase inhibitor that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the patient treated and the particular mode of administration.Preferably, the compositions should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of the inhibitor can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

Depending upon the particular protein kinase-mediated condition to betreated or prevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may be administeredtogether with the inhibitors of this invention. For example, in thetreatment of diabetes other anti-diabetic agents may be combined withthe GSK-3 inhibitors of this invention to treat diabetes. These agentsinclude, without limitation, insulin or insulin analogues, in injectableor inhalation form, glitazones, alpha glucosidase inhibitors,biguanides, insulin sensitizers, and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation, chemotherapeutic agents orother anti-proliferative agents such as adriamycin, dexamethasone,vincristine, cyclophosphamide, fluorouracil, topotecan, taxol,interferons, and platinum derivatives; anti-inflammatory agents such ascorticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; immunomodulatory and immunosuppressive agents such ascyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

Those additional agents may be administered separately from the proteinkinase inhibitor-containing composition, as part of a multiple dosageregimen. Alternatively, those agents may be part of a single dosageform, mixed together with the protein kinase inhibitor of this inventionin a single composition.

Compounds of this invention may exist in alternative tautomeric forms,as in tautomers 1 and 2 shown below. Unless otherwise indicated, therepresentation of either tautomer is meant to include the other.

R^(x) and R^(y) (at positions Z³ and Z⁴, respectively) may be takentogether to form a fused ring, providing a bicyclic ring systemcontaining Ring A. Preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.Examples of Ring A systems are shown below by compounds I-A throughI-DD, wherein Z¹ is nitrogen or C(R⁹) and Z² is nitrogen or C(H).

Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D, I-E, I-F,I-G, I-H, I-I, I-J, I-K, I-L, and I-M, more preferably I-A, I-B, I-C,I-F, and I-H, and most preferably I-A, I-B, and I-H.

In the monocyclic Ring A system, preferred R^(x) groups, when present,include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄ aliphaticgroup such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.Preferred R^(y) groups, when present, include T—R³ wherein T is avalence bond or a methylene, and R³ is —R, —N(R⁴)₂, or —OR. Examples ofpreferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

In the bicyclic Ring A system, the ring formed when R^(x) and R^(y) aretaken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.

Preferred R^(x)/R^(y) ring substituents include -halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

R² and R^(2′) may be taken together to form a fused ring, thus providinga bicyclic ring system containing a pyrazole ring. Preferred fused ringsinclude benzo, pyrido, pyrimido, and a partially unsaturated 6-memberedcarbocyclo ring, wherein said fused ring is optionally substituted.These are exemplified in the following formula I compounds having apyrazole-containing bicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: -halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl, —NO₂,—O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl), —CN, —SO₂(C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl) is most preferably methyl.

When the pyrazole ring system is monocyclic, preferred R² groups includehydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substituted phenyl,hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

An embodiment that is particularly useful for treating GSK3-mediateddiseases relates to compounds of formula II:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R₄;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶.

When the R^(x) and R^(y) groups of formula II are taken together to forma fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula II are themono- and bicyclic systems shown below.

More preferred pyrimidine ring systems of formula II include II-A, II-B,II-C, II-F, and II-E, most preferably II-A, II-B, and II-H.

In the monocyclic pyrimidine ring system of formula II, preferred R^(x)groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups include T—R³ wherein T is a valence bondor a methylene, and R³ is —R, —N(R⁴)₂, or —OR. When R³ is —R or —OR, apreferred R is an optionally substituted group selected from C₁₋₆aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring.Examples of preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula II, the ring formedwhen R^(x) and R^(y) are taken together may be substituted orunsubstituted. Suitable substituents include —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂, (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are asdefined above. Preferred R^(x)/R^(y) ring substituents include -halo,—R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is anoptionally substituted C₁₋₆ aliphatic group.

The R² and R^(2′) groups of formula II may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula II compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula II includeone or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula II is monocyclic, preferred R²groups include hydrogen, a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include methyl, t-butyl, —CH₂OCH₃, cyclopropyl,furanyl, thienyl, and phenyl. A preferred R² group is hydrogen.

More preferred ring systems of formula II are the following, which maybe substituted as described above, wherein R² and R^(2′) are takentogether with the pyrazole ring to form an indazole ring; and R^(x) andR^(y) are each methyl, or R^(x) and R^(y) are taken together with thepyrimidine ring to form a quinazoline or tetrahydroquinazoline ring:

Particularly preferred are those compounds of formula II-Aa, II-Ba, orII-Ha wherein ring C is a phenyl ring and R¹ is halo, methyl, ortrifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When twoadjacent substituents on Ring C are taken together to form a fused ring,Ring C is contained in a bicyclic ring system. Preferred fused ringsinclude a benzo or pyrido ring. Such rings preferably are fused at orthoand meta positions of Ring C. Examples of preferred bicyclic Ring Csystems include naphthyl, quinolinyl and isoquinolinyl.

An important feature of the formula II compounds is the R¹ orthosubstituent on Ring C. An ortho position on Ring C or Ring D is definedrelative to the position where Ring A is attached. Preferred R¹ groupsinclude -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶. When R¹ is an optionally substituted C₁₋₆aliphatic group, the most preferred optional substituents are halogen.Examples of preferred R¹ groups include —CF₃, —Cl, —F, —CN, —COCH₃,—OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃, cyclohexyl, t-butyl,isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃, —SO₂NH₂, —N(CH₃)₂,—CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and —OCF₃.

On Ring C of formula II, preferred R⁵ substituents, when present,include -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and—N(R⁴)SO₂R. More preferred R⁵ substituents include —Cl, —F, —CN, —CF₃,—NH₂, —NH(C₁₋₄ aliphatic), —N(C₁-₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic). Examples of such preferred R⁵substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and —CO₂Et.

Preferred-formula II compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 0-2 ring nitrogens;

(c) R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶; and

(d) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula II have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma 5-7 membered unsaturated or partially unsaturated carbocyclo ringoptionally substituted with —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

(c) R¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group,phenyl, or —CN;

(d) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

(e) each R⁵ is independently selected from -halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

Even more preferred compounds of formula II have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl ring optionally substituted by —R⁵;

(b) R^(x) is hydrogen or methyl and R^(y) is methyl, methoxymethyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionallysubstituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, orphenyl, or R^(x) and R^(y) are taken together with their interveningatoms to form an optionally substituted benzo ring or partiallyunsaturated 6-membered carbocyclo ring;

(c) R¹ is -halo, a C₁₋₄ aliphatic group optionally substituted withhalogen, or —CN;

(d) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

(e) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃, —NH₂,—NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic).

Representative compounds of formula II are shown below in Table 1.

TABLE 1

II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

II-12

II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

II-57

II-58

II-59

II-60

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

II-70

II-71

II-72

II-73

II-74

II-75

II-76

II-77

II-78

II-79

II-80

II-81

II-82

II-83

II-84

II-85

II-86

II-87

II-88

II-89

II-90

II-91

II-92

II-93

II-94

II-95

II-96

II-97

II-98

II-99

II-100

II-101

II-102

II-103

II-104

II-105

II-106

II-107

II-108

II-109

II-110

II-111

II-112

II-113

II-114

II-115

II-116

II-117

II-118

II-119

II-120

II-121

II-122

II-123

II-124

II-125

II-126

II-127

II-128

II-129

II-130

II-131

II-132

II-133

II-134

II-135

II-136

II-137

II-138

II-139

II-140

II-141

II-142

II-143

II-144

II-145

II-146

II-147

II-148

II-149

II-150

II-151

II-152

II-153

II-154

II-155

II-156

II-157

II-158

II-159

II-160

II-161

II-162

II-163

II-164

II-165

II-166

II-167

II-168

II-169

II-170

II-171

II-172

II-173

II-174

II-175

II-176

II-177

II-178

II-179

II-180

II-181

II-182

II-183

II-184

II-185

II-186

II-187

II-188

II-189

II-190

II-191

II-192

II-193

II-194

II-195

II-196

II-197

II-198

II-199

II-200

II-201

II-202

II-203

II-204

II-205

II-206

II-207

II-208

II-209

II-210

II-211

II-212

II-213

II-214

II-215

II-216

II-217

II-218

II-219

II-220

II-221

II-222

II-223

II-224

II-225

II-226

II-227

II-228

II-229

II-230

II-231

II-232

II-233

II-234

II-235

II-236

II-237

II-238

II-239

II-240

II-241

II-242

II-243

II-244

II-245

II-246

II-247

II-248

II-249

II-250

II-251

In another embodiment, this invention provides a composition comprisinga compound of formula II and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula II. This methodis especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula II. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula II. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula II.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula II. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula II, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula II, asdescribed above.

Another embodiment of this invention relates to compounds of formulaIII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused, benzo ring or a 5-8 membered carbocyclo ring, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Preferred formula III Ring D monocyclic rings include substituted andunsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl,thienyl, azepanyl, and morpholinyl rings. When two adjacent substituentson Ring D are taken together to form a fused ring, the Ring D system isbicyclic. Preferred formula III Ring D bicyclic rings include1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring Dsystems include naphthyl and isoquinolinyl.

Preferred R⁵ substituents on Ring D of formula III include halo, oxo,CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴) —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—SR, —OR, —C(O)R, or substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. More preferredR⁵ substituents include -halo, —CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, ora substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples of Ring Dsubstituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH, pyrrolidinyl,OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl, tert-butyl, SEt,OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

Preferred rings formed when the R^(x) and R^(y) groups of formula IIIare taken together to form a fused ring include a 5-, 6-, or 7-memberedunsaturated or partially unsaturated carbocyclo ring, wherein anysubstitutable carbon on said fused ring is substituted by oxo or T—R³.Examples of preferred bicyclic ring systems are shown below.

Preferred substituents on the R^(x)/R^(y) fused ring of formula IIIinclude —R, oxo, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R,—SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N (R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,wherein R and R⁴ are as defined above. More preferred substituents onthe R^(x)/R^(y) fused ring include halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- ordialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl. Examples of suchpreferred substituents include methoxy, methyl, isopropyl,methylsulfonyl, cyano, chloro, pyrrolyl, methoxy, ethoxy, ethylamino,acetyl, and acetamido.

Preferred R² substituents of formula III include hydrogen, C₁₋₄aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl,alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, —CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl).

When the R² and R^(2′) groups of formula III are taken together to forma ring, preferred R²/R^(2′) ring systems containing the pyrazole ringinclude benzo, pyrido, pyrimido, 3-oxo-2H-pyridazino, and a partiallyunsaturated 6-membered carbocyclo ring. Examples of such preferredR²/R^(2′) ring systems containing the pyrazole ring include thefollowing:

Preferred substituents on the R²/R^(2′) fused ring of formula IIIinclude one or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

Preferred formula III compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from a phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) and R^(y) are taken together with their intervening atoms toform an optionally substituted benzo ring or a 5-7 membered carbocycloring; and

(c) R^(2′) is hydrogen or methyl and R² is T—W—R⁶ or R, wherein W is—C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁵)—, and R is an optionally substitutedgroup selected from C₁₋₆ aliphatic or phenyl, or R² and R^(2′) are takentogether with their intervening atoms to form a substituted orunsubstitutedbenzo, pyrido, pyrimido, or partially unsaturated6-membered carbocyclo ring.

More preferred compounds of formula III have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or a 5-7 membered carbocyclo ring optionallysubstituted with —R, oxo, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂; and

(c) each R⁵ is independently selected from halo, oxo, CN, NO₂, —N(R⁴)₂,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R,or a substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

Even more preferred compounds of formula III have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a benzo or 6-membered partially unsaturated carbocyclo ringoptionally substituted with halo, CN, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy,(C₁₋₆alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- or dialkylamino, mono-or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6membered heteroaryl;

(b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆-₁₀ aryl, or C₁₋₆ aliphatic; and

(c) R^(2′) is hydrogen and R² is selected from R^(2′) is hydrogen ormethyl and R² is T—W—R⁶ or R, wherein W is —C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—,—CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, or —CON(R⁶)—, and R is anoptionally substituted group selected from C₁₋₆ aliphatic or phenyl, orR² and R^(2′) are taken together with their intervening atoms to form abenzo, pyrido, or partially unsaturated 6-membered carbocyclo ringoptionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁-₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group.

Representative compounds of formula III are set forth in Table 2 below.

TABLE 2

III-1

III-2

III-3

III-4

III-5

III-6

III-7

III-8

III-9

III-10

III-11

III-12

III-13

III-14

III-15

III-16

III-17

III-18

III-19

III-20

III-21

III-22

III-23

III-24

III-25

III-26

III-27

III-28

III-29

III-30

III-31

III-32

III-33

III-34

III-35

III-36

III-37

III-38

III-39

III-40

III-41

III-42

III-43

III-44

III-45

III-46

III-47

III-48

III-49

III-50

III-51

III-52

III-53

III-54

III-55

III-56

III-57

III-58

III-59

III-60

III-61

III-62

III-63

III-64

III-65

III-66

III-67

III-68

III-69

III-70

III-71

III-72

III-73

III-74

III-75

III-76

III-77

III-78

III-79

III-80

III-81

III-82

III-83

III-84

III-85

III-86

III-87

III-88

III-89

III-90

III-91

III-92

III-93

III-94

III-95

III-96

III-97

III-98

III-99

III-100

III-101

III-102

III-103

III-104

III-105

III-106

III-107

III-108

III-109

III-110

III-111

III-112

III-113

III-114

III-115

III-116

III-117

III-118

III-119

III-120

III-121

III-122

III-123

III-124

III-125

III-126

III-127

III-128

III-129

III-130

III-131

III-132

III-133

III-134

III-135

III-136

III-137

III-138

III-139

III-140

III-141

III-142

III-143

III-144

III-145

III-146

In another embodiment, this invention provides a composition comprisinga compound of formula III and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula III. Thismethod is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula III. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula III. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

One aspect of this invention relates to a method of inhibiting Srcactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula III.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a Src inhibitor, said method comprising thestep of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula III. This method is especially useful for treatinghypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatictreatment of bone metastasis, and Paget's disease.

Another method relates to inhibiting GSK-3, Aurora, CDK-2, or Srcactivity in a biological sample, which method comprises contacting thebiological sample with the GSK-3, Aurora, CDK-2, or Src inhibitor offormula III, or a pharmaceutical composition thereof, in an amounteffective to inhibit GSK-3, Aurora, CDK-2, or Src.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora, CDK-2, or Src, or the treatment of a disease alleviated thereby,is preferably carried out with a preferred compound of formula III, asdescribed above.

Compounds of formula III, wherein R^(2′) is hydrogen and R^(x) and R^(y)are taken together with the pyrimidine ring to form an optionallysubstituted quinazoline ring system, are also inhibitors of ERK-2 andAKT protein kinases.

Accordingly, another method of this invention relates to a method ofinhibiting ERK-2 or AKT activity in a patient, comprising administeringto the patient a therapeutically effective amount of a compositioncomprising a compound of formula III, wherein R² is hydrogen and R^(x)and R^(y) are taken together with the pyrimidine ring to form anoptionally substituted quinazoline ring system.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a ERK-2 or AKT inhibitor, said methodcomprising the step of administering to a patient in need of such atreatment a therapeutically effective amount of a composition comprisinga compound of formula III, wherein R^(2′) is hydrogen and R^(x) andR^(y) are taken together with the pyrimidine ring to form an optionallysubstituted quinazoline ring system. This method is especially usefulfor treating cancer, stroke, hepatomegaly, cardiovascular disease,Alzheimer's disease, cystic fibrosis, viral disease, autoimmunediseases, restenosis, psoriasis, allergic disorders including asthma,inflammation, and neurological disorders.

Another embodiment of this invention relates to compounds of formula IV:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring is optionally and independentlysubstituted by T—R³, and any substitutable nitrogen on said ring issubstituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring containing 0-3ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein saidfused ring is optionally substituted by up to three groups independentlyselected from halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶;

R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷ —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂ or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN (R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclylring or heteroaryl.

Preferred formula IV Ring D monocyclic rings include substituted andunsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl,thienyl, azepanyl, and morpholinyl rings. Preferred formula IV Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred Ring D bicyclic rings include naphthyl andisoquinolinyl.

Preferred substituents on Ring D of formula IV include halo, oxo, CN,—NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR,—OR, —C(O)R, or substituted or unsubstituted group selected from 5-6membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. More preferred R⁵substituents include -halo, —CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or asubstituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples of Ring Dsubstituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH, pyrrolidinyl,OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl, tert-butyl, SEt,OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

When the R^(x) and R^(y) groups of formula IV are taken together to forma fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or8-membered unsaturated or partially unsaturated ring having 1-2heteroatoms. This provides a bicyclic ring system containing thepyrimidine ring. Examples of preferred pyrimidine ring systems offormula IV are the mono- and bicyclic systems shown below.

More preferred pyrimidine ring systems of formula IV include IV-E, IV-G,IV-H, IV-J, IV-K, IV-L, IV-M, IV-T, and IV-U.

In the monocyclic pyrimidine ring system of formula IV, preferred R^(x)groups include hydrogen, amino, nitro, alkyl- or dialkylamino,acetamido, or a C₁₋₄ aliphatic group such as methyl, ethyl, cyclopropyl,isopropyl or t-butyl. Preferred R^(y) groups include T—R³ wherein T is avalence bond or a methylene, and R³ is —R, —N(R⁴)₂ or —OR. When R³ is —Ror —OR, a preferred R is an optionally substituted group selected fromC₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclylring. Examples of preferred R^(y) groups include 2-pyridyl, 4-pyridyl,piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- ordialkylamino, acetamido, optionally substituted phenyl such as phenyl,methoxyphenyl, trimethoxyphenyl, or halo-substituted phenyl, andmethoxymethyl.

In the bicyclic pyrimidine ring system of formula IV, the ring formedwhen R^(x) and R^(y) are taken together may be substituted orunsubstituted. Suitable substituents include —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substitutedC₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are asdefined above for compounds of formula IV. Preferred R^(x)/R^(y) ringsubstituents include -halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or—N(R⁴)₂ wherein R is a substituted or unsubstituted C₁₋₆ aliphaticgroup.

The R² and R^(2′) groups of formula IV may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula IV compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula IV includeone or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁-₄ alkyl) group ismethyl.

When the pyrazole ring system of formula IV is monocyclic, preferred R²groups include hydrogen, a substituted or unsubstituted group selectedfrom aryl, heteroaryl, or a C₁₋₆ aliphatic group. Examples of suchpreferred R² groups include methyl, t-butyl, —CH₂OCH₃, cyclopropyl,furanyl, thienyl, and phenyl. A preferred R^(2′) group is hydrogen.

Preferred formula IV compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from a phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 1-2 ring heteroatoms; and

(c) R^(2′) is hydrogen or methyl and R² is T—W—R⁶ or R, wherein W is—C(R⁶)₂O—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, or —CON(R⁶)—, and R is an optionally substitutedgroup selected from C₁₋₆ aliphatic or phenyl, or R² and R^(2′) are takentogether with their intervening atoms to form a substituted orunsubstituted benzo, pyrido, pyrimido, or partially unsaturated6-membered carbocyclo ring.

More preferred compounds of formula IV have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma 5-7 membered unsaturated or partially unsaturated ring having 1-2 ringnitrogens, wherein said ring is optionally substituted with —R, halo,oxo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N (R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;and

(c) each R⁵ is independently selected from halo, oxo, CN, NO₂, —N(R⁴)₂,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R,or a substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

Even more preferred compounds of formula IV have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a 6-membered unsaturated or partially unsaturated ring having 1-2ring nitrogens, optionally substituted with halo, CN, oxo, C₁₋₆ alkyl,C₁₋₆ alkoxy, (C₁₋₆alkyl)carbonyl, (C₁₋₆alkyl)sulfonyl, mono- ordialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

(c) R^(2′) is hydrogen and R² is T—W—R⁶ or R, wherein W is —C(R⁶)₂O—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)₂N(R⁶)CO—, or —CON(R⁶)—,and R is an optionally substituted group selected from C₁₋₆ aliphatic orphenyl, or R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, or partially unsaturated 6-membered carbocycloring optionally substituted with -halo, oxo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group.

Representative compounds of formula IV are set forth in Table 3 below.

TABLE 3

In another embodiment, this invention provides a composition comprisinga compound of formula IV and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula IV. This methodis especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula IV. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula IV. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IV.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IV. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula IV, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IV, asdescribed above.

Another embodiment of this invention relates to compounds of formula V:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is N, CR^(a), or CH and Z² is N or CH, provided that one of Z¹ and Z²is nitrogen;

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷) CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷, or two R⁴ on thesame nitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R , or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N (R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶) SO₂N(R⁶)—, or —C (R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N (R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

R^(a) is selected from halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N (R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R,—OC(═O)N(R⁴)₂, or an optionally substituted group selected from C₁₋₆aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms.

Compounds of formula V may be represented by specifying Z¹ and Z² asshown below:

When the R^(x) and R^(y) groups of formula V are taken together to forma fused ring, preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or8-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyridine ring.Examples of preferred bicyclic ring systems of formula V are shownbelow.

More preferred bicyclic ring systems of formula V include Va-A, Vb-A,Vc-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb-E, Vc-E, Va-J, Vb-J,Vc-J, Va-K, Vb-K, Vc-K, Va-L, Vb-L, Vc-L, Va-M, Vb-M, and Vc-M, mostpreferably Va-A, Vb-A, Vc-A, Va-B, Vb-B, and Vc-B.

In the monocyclic pyridine ring system of formula V, preferred R^(x)groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl ort-butyl. Preferred R^(y) groups include T—R³ wherein T is a valence bondor a methylene, and R³ is —R, —N(R⁴)₂, or —OR. When R³ is —R or —OR, apreferred R is an optionally substituted group selected from C₁₋₆aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring.Examples of preferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl,methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

In the bicyclic ring system of formula V, the ring formed when R^(x) andR^(y) are taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include -halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is an optionally substituted C₁₋₆aliphatic group.

The R² and R^(2′) groups of formula V may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula V compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring of formula V includeone or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system is monocyclic, preferred R² groups includehydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substituted phenyl,hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON (Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

More preferred ring systems of formula V are the following, which may besubstituted as described above, wherein R² and R^(2′) are taken togetherwith the pyrazole ring to form an optionally substituted indazole ring;and R^(x) and R^(y) are each methyl, or R^(x) and R^(y) are takentogether with the pyridine ring to form an optionally substitutedquinoline, isoquinoline, tetrahydroquinoline or tetrahydroisoquinolinering:

When G is Ring C, preferred formula V Ring C groups are phenyl andpyridinyl. When two adjacent substituents on Ring C are taken togetherto form a fused ring, Ring C is contained in a bicyclic ring system.Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

On Ring C preferred R⁵ substituents, when present, include -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. More preferredR⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic). Examples of such preferred R⁵ substituents include —Cl, —F,—CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, and —CO₂Et.

When G is Ring D, preferred formula V Ring D monocyclic rings includesubstituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula V Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

Preferred substituents on Ring D of formula V include one or more of thefollowing: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

Preferred formula V compounds have one or more, and more preferably all,of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or iso quinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 0-2 ring nitrogens; and

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula V have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma benzo ring or a 5-7 membered partially unsaturated carbocyclo ring,said benzo or carbocyclo ring optionally substituted with —R, halo, —OR,—C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,or —N(R⁴)SO₂R.

Even more preferred compounds of formula V have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(b) R^(x) is hydrogen or methyl and R^(y) is methyl, methoxymethyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionallysubstituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, orphenyl, or R^(x) and R^(y) are taken together with their interveningatoms to form a benzo ring or a 6-membered partially unsaturatedcarbocyclo ring optionally substituted with halo, CN, oxo, C₁₋₆ alkyl,C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- ordialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(c) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).

Representative compounds of formula V are set forth in Table 4 below.

TABLE 4

In another embodiment, this invention provides a composition comprisinga compound of formula V and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula V. This methodis especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula V. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula V. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V. This method is especially useful for treating cancer, suchas colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula V.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula V. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula V, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula V, asdescribed above.

Another embodiment of this invention relates to compounds of formula VI:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(y) is T—R^(3′);

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R² issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

R^(3′) is an optionally substituted group selected from C₁₋₆ aliphatic,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms,or a heterocyclyl ring having 5-10 ring atoms;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴) N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O) N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶))C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶.

Preferred R^(y) groups of formula VI include T—R^(3′) wherein T is avalence bond or a methylene, and R^(3′) is an optionally substitutedgroup selected from C₁₋₆ aliphatic, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, aheteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having5-10 ring atoms. A preferred R^(3′) group is an optionally substitutedgroup selected from C₃₋₆ carbocyclyl, phenyl, or a 5-6 memberedheteroaryl or heterocyclyl ring. Examples of preferred R^(y) include2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl,and optionally substituted phenyl such as phenyl or halo-substitutedphenyl.

The R² and R^(2′) groups of formula VI may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula VI compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO₂,—O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When the pyrazole ring system is monocyclic, preferred R² groups offormula VI include hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl,(un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono-or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH (CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

When G is Ring C, preferred formula VI Ring C groups are phenyl andpyridinyl. When two adjacent substituents on Ring C are taken togetherto form a fused ring, Ring C is contained in a bicyclic ring system.Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

On Ring C preferred R⁵ substituents, when present, include -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. More preferredR⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic). Examples of such preferred R⁵ substituents include —Cl, —F,—CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, and —CO₂Et.

When G is Ring D, preferred formula VI Ring D monocyclic rings includesubstituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VI Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

Preferred substituents on formula VI Ring D include one or more of thefollowing: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

Preferred formula VI compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring C is selected from a phenyl or pyridinyl ring, optionallysubstituted by —R⁵, wherein when Ring C and two adjacent substituentsthereon form a bicyclic ring system, the bicyclic ring system isselected from a naphthyl, quinolinyl or isoquinolinyl ring, and R¹ is-halo, an optionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶,—OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂,or —NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(y) is T—R^(3′), wherein T is a valence bond or a methylene; and

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VI have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(y) is T—R^(3′), wherein T is a valence bond or a methylene and R³is an optionally substituted group selected from C₁₋₆ aliphatic, C₃₋₆carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms;

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,or —N(R⁴)SO₂R.

Even more preferred compounds of formula VI have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R^(3′), wherein T is a valence bond or a methylene andR^(3′) is an optionally substituted group selected from C₁₋₄ aliphatic,C₃₋₆ carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclylring;

(b) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(c) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).

Another embodiment of this invention relates to compounds of formulaVIa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

T is a valence bond or a C₁₋₄ alkylidene chain;

R and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶), —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶) N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶.

Preferred rings formed by the R² and R^(2′) groups of formula Viainclude benzo, pyrido, pyrimido, and a partially unsaturated 6-memberedcarbocyclo ring. These are exemplified in the following formula VIacompounds having a pyrazole-containing bicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl, —NO₂,—O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When G is Ring C, preferred formula VIa Ring C groups are phenyl andpyridinyl. When two adjacent substituents on Ring C are taken togetherto form a fused ring, Ring C is contained in a bicyclic ring system.Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R₁ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

On Ring C preferred R⁵ substituents, when present, include -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. More preferredR⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic). Examples of such preferred R⁵ substituents include —Cl, —F,—CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, and —CO₂Et.

When G is Ring D, preferred formula VIa Ring D monocyclic rings includesubstituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VIa Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

Preferred substituents on the formula Via Ring D include one or more ofthe following: halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴),—N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted orunsubstituted group selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl,or C₁₋₆ aliphatic. More preferred Ring D substituents include -halo,—CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, or a substituted or unsubstitutedgroup selected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆aliphatic. Examples of Ring D substituents include —OH, phenyl, methyl,CH₂OH, CH₂CH₂OH, pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂,C(O)CH₃, i-propyl, tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, andethylene dioxy.

Preferred formula VIa compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and

(b) R² and R^(2′) are taken together with their intervening atoms toform a substituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(Cl₄alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

(c) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,or —N(R⁴)SO₂R.

Even more preferred compounds of formula VIa have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(b) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, or partially unsaturated 6-membered carbocycloring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).

Representative compounds of formula VI and IVa are set forth in Table 5below.

TABLE 5

In another embodiment, this invention provides a composition comprisinga compound of formula VI or VIa and a pharmaceutically acceptablecarrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VI or VIa. Thismethod is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VI or VIa. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula VI or VIa. This method is especially useful fortreating schizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa. This method is especially useful for treatingcancer, such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VI or VIa. This method is especially useful for treatingcancer, Alzheimer's disease, restenosis, angiogenesis,glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis,atherosclerosis, alopecia, and autoimmune diseases such as rheumatoidarthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula VI or VIa, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula VI or VIa,as described above.

Another embodiment of this invention relates to compounds of formulaVII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(y) is hydrogen or T—R^(3″);

T is a valence bond, hydrogen, or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R² is substitutedby R⁴;

R^(3″) is selected from an optionally substituted group selected fromC₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms,or a heterocyclyl ring having 5-10 ring atoms;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O) N(R⁶)—, —OC(O) N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁵),—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O) N(R⁴)₂.

Preferred R^(y) groups of formula VII include T—R^(3″) wherein T is avalence bond or a methylene. Preferred R^(3″) groups include anoptionally substituted group selected from C₃₋₆ carbocyclyl, phenyl, ora 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferredR^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl, and anoptionally substituted phenyl such as phenyl or halo-substituted phenyl.

The R² and R^(2′) groups of formula VII may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula VII compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the R²/R^(2′) fused ring include one or moreof the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄ haloalkyl , —NO₂,—O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂, and—CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched, orcyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

When the pyrazole ring system of formula VII is monocyclic, preferred R²groups include hydrogen , C₁₋₄ aliphatic, alkoxycarbonyl,(un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono-or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

When G is Ring C, preferred formula VII Ring C groups are phenyl andpyridinyl. When two adjacent substituents on Ring C are taken togetherto form a fused ring, Ring C is contained in a bicyclic ring system.Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂, —N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

On Ring C preferred R⁵ substituents, when present, include -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. More preferredR⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic). Examples of such preferred R⁵ substituents include —Cl, —F,—CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl, cyclopropyl,isopropyl, t-butyl , and —CO₂Et.

When G is Ring D, preferred formula VII Ring D monocyclic rings includesubstituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VII Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

Preferred substituents on Ring D include one or more of the following:halo, oxo, CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —SR, —OR, —C(O)R, or substituted or unsubstituted groupselected from 5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.More preferred Ring D substituents include -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples ofRing D substituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH,pyrrolidinyl, OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl,tert-butyl, SEt, OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

Preferred formula VII compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O) NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(y) is T—R^(3″), wherein T is a valence bond or a methylene; and

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(y) is T—R^(3″), wherein T is a valence bond or a methylene andR^(3″) is an optionally substituted group selected from C₃₋₆carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring;

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, or a C₁₋₆ aliphatic group, or R²and R^(2′) are taken together with their intervening atoms to form asubstituted or unsubstituted benzo, pyrido, pyrimido or partiallyunsaturated 6-membered carbocyclo ring; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from -halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆aliphatic group, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂,or —N(R⁴)SO₂R.

Even more preferred compounds of formula VII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(y) is T—R^(3″), wherein T is a valence bond or a methylene andR^(3″) is an optionally substituted group selected from phenyl, or a 5-6membered heteroaryl or heterocyclyl ring;

(b) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(c) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and

(d) Ring D is substituted by oxo or R⁵, wherein each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH (C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).

Representative compounds of formula VII are set forth in Table 6 below.

TABLE 6

In another embodiment, this invention provides a composition comprisinga compound of formula VII and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VII. Thismethod is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VII. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula VII. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VII. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula VII, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula VII, asdescribed above.

Another embodiment of this invention relates to compounds of formulaVIII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is N or CR⁹, Z² is N or CH, and Z³ is N or CR^(x), provided that oneof Z¹ and Z² is nitrogen;

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by halo, oxo, or —R⁵, and at any substitutablering nitrogen by —R⁴, provided that when Ring D is a six-membered arylor heteroaryl ring, —R⁵ is hydrogen at each ortho carbon position ofRing D;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) is T—R³;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R² andR^(2′) are taken together with their intervening atoms to form a fused,5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable carbon on said fused ring formed by R² and R^(2′) issubstituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, and anysubstitutable nitrogen on said ring formed by R² and R^(2′) issubstituted by R⁴;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Accordingly, the present invention relates to compounds of formulaVIIIa, VIIIb, VIIIc and VIIId as shown below:

Preferred R^(x) groups of formula VIII include T—R³ wherein T is avalence bond or a methylene and R³ is CN, —R, or —OR. When R³ is —R,preferred R³ groups include an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl orheterocyclyl ring. When R³ is —OR, preferred R groups include anoptionally substituted group C₁₋₆ aliphatic group such as alkyl- ordialkylaminoalkyl and aminoalkyl. Examples of preferred R^(x) includeacetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl,imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl,isopropyl, t-butyl, NH₂CH₂CH₂NH, and NH₂CH₂CH₂O.

Preferred R⁹ groups of formula VIII, when present, include R, OR, andN(R⁴)₂. Examples of preferred R⁹ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

The R² and R^(2′) groups of formula VIII may be taken together to form afused ring, thus providing a bicyclic ring system containing a pyrazolering. Preferred fused rings include benzo, pyrido, pyrimido, and apartially unsaturated 6-membered carbocyclo ring. These are exemplifiedin the following formula VIII compounds having a pyrazole-containingbicyclic ring system:

Preferred substituents on the formula VIII R²/R^(2′) fused ring includeone or more of the following: -halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

When the pyrazole ring system of formula VIII is monocyclic, preferredR² groups include hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl,(un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono-or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

When G is Ring C, preferred formula VIII Ring C groups are phenyl andpyridinyl. When two adjacent substituents on Ring C are taken togetherto form a fused ring, Ring C is contained in a bicyclic ring system.Preferred fused rings include a benzo or pyrido ring. Such ringspreferably are fused at ortho and meta positions of Ring C. Examples-ofpreferred bicyclic Ring C systems include naphthyl and isoquinolinyl.Preferred R¹ groups include -halo, an optionally substituted C₁₋₆aliphatic group, phenyl, —COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂,—CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or —NHSO₂R⁶. When R¹ is anoptionally substituted C₁₋₆ aliphatic group, the most preferred optionalsubstituents are halogen. Examples of preferred R¹ groups include —CF₃,—Cl, —F, —CN, —COCH₃, —OCH₃, —OH, —CH₂CH₃, —OCH₂CH₃, —CH₃, —CF₂CH₃,cyclohexyl, t-butyl, isopropyl, cyclopropyl, —C—≡CH, —C≡C—CH₃, —SO₂CH₃,—SO₂NH₂-N(CH₃)₂, —CO₂CH₃, —CONH₂, —NHCOCH₃, —OC(O)NH₂, —NHSO₂CH₃, and—OCF₃.

On Ring C preferred R⁵ substituents, when present, include -halo, —CN,—NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R. More preferredR⁵ substituents include —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic),—N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic). Examples of such preferred R⁵ substituents include —Cl, —F,—CN, —CF₃, —NH₂, —NHMe, —NMe₂, —OEt, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, and —CO₂Et.

When G is Ring D, preferred formula VIII Ring D monocyclic rings includesubstituted and unsubstituted phenyl, pyridinyl, piperidinyl,piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.When two adjacent substituents on Ring D are taken together to form afused ring, the Ring D system is bicyclic. Preferred formula VIII Ring Dbicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl.Examples of more preferred bicyclic Ring D systems include naphthyl andisoquinolinyl.

Preferred R⁵ substituents on Ring D of formula VIII include halo, oxo,CN, —NO₂, —N(R⁴)₂, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—SR, —OR, —C(O)R, or substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. More preferredR⁵ substituents include -halo, —CN, -oxo, —SR, —OR, —N(R⁴)₂, —C(O)R, ora substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic. Examples of Ring Dsubstituents include —OH, phenyl, methyl, CH₂OH, CH₂CH₂OH, pyrrolidinyl,OPh, CF₃, C≡CH, Cl, Br, F, I, NH₂, C(O)CH₃, i-propyl, tert-butyl, SEt,OMe, N(Me)₂, methylene dioxy, and ethylene dioxy.

Preferred formula VIII compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) is T—R³ wherein T is a valence bond or a methylene; and

(c) R^(2′) is hydrogen and R² is hydrogen or a substituted orunsubstituted group selected from aryl, heteroaryl, or a C₁₋₆ aliphaticgroup, or R² and R^(2′) are taken together with their intervening atomsto form a substituted or unsubstituted benzo, pyrido, pyrimido orpartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VIII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) is T—R³ wherein T is a valence bond or a methylene and R³ isCN, —R or —OR;

(c) R² is hydrogen and R² is hydrogen or a substituted or unsubstitutedgroup selected from aryl, or a C₁₋₆ aliphatic group, or R² and R^(2′)are taken together with their intervening atoms to form a substituted orunsubstituted benzo, pyrido, pyrimido or partially unsaturated6-membered carbocyclo ring; and

(d) each R⁵ is independently selected from -halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂ or —N(R⁴)SO₂R.

Even more preferred compounds of formula VIII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is T—R³ wherein T is a valence bond or a methylene and R³ is—R or —OR wherein R is an optionally substituted group selected fromC₁₋₆ aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclylring;

(b) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoguinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(c) R² and R^(2′) are taken together with their intervening atoms toform a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂₁ or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group;

(d) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃, —NH₂,—NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and CO₂(C₁₋₄ aliphatic); and

(e) R⁹ is R, OR, or N(R⁴)₂.

Representative compounds of formula VIII are set forth in Table 7 below.

TABLE 7

In another embodiment, this invention provides a composition comprisinga compound of formula VIII and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula VIII. Thismethod is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula VIII. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula VIII. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula VIII.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a CDK-2 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula VIII. This method is especially useful for treating cancer,Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, andautoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity ina biological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula VIII, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3,Aurora or CDK-2, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula VIII, asdescribed above.

The above formula I compounds contain a pyrazole ring bearing the R² andR^(2′) substituents. In their search for further inhibitors of theprotein kinases GSK and Aurora, applicants sought to replace thepyrazole moiety of formula I with other heteroaromatic rings. One of themore effective pyrazole ring replacements was found to be a triazolering. Inhibitors having this triazole ring are otherwise structurallysimilar to the formula I compounds and are represented by the generalformula IX:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen or CR⁹ and Z² is nitrogen or CH, provided that at leastone of Z¹ and Z² is nitrogen;

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —Rl, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂,T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² is —R or —T—W—R⁶;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R)N(R⁵)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

R⁹ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂.

Compounds of formula IX may exist in alternative tautomeric forms, as intautomers 1-3 shown below. Unless otherwise indicated, therepresentation of any of these tautomers is meant to include the othertwo.

The R^(x) and R^(y) groups of formula IX may be taken together to form afused ring, providing a bicyclic ring system containing Ring A.Preferred R^(x)/R^(y) rings include a 5-, 6-, 7-, or 8-memberedunsaturated or partially unsaturated ring having 0-2 heteroatoms,wherein said R^(x)/R^(y) ring is optionally substituted. Examples ofRing A systems are shown below by compounds IX-A through IX-DD, whereinZ¹ is nitrogen or C(R⁹) and Z² is nitrogen or C(H).

Preferred bicyclic Ring A systems of formula IX include IX-A, IX-B,IX-C, IX-D, IX-E, IX-F, IX-G, IX-H, IX-I, IX-J, IX-K, IX-L, and IX-M,more preferably IX-A, IX-B, IX-C, IX-F, and IX-H, and most preferablyIX-A, IX-B, and IX-H.

In the monocyclic Ring A system of formula IX, preferred R^(x) groupsinclude hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄ aliphaticgroup such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.Preferred R^(y) groups, when present, include T—R³ wherein T is avalence bond or a methylene, and R³ is —R, —N(R⁴)₂, or —OR. Examples ofpreferred R^(y) include 2-pyridyl, 4-pyridyl, piperidinyl, methyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino,acetamido, optionally substituted phenyl such as phenyl orhalo-substituted phenyl, and methoxymethyl.

In the bicyclic Ring A system of formula IX, the ring formed by R^(x)and R^(y) taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.

Preferred R^(x)/R^(y) ring substituents include -halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂ wherein R is an optionally substitutedC₁₋₆ aliphatic group.

Preferred R² groups of formula IX include hydrogen, C₁₋₄ aliphatic ,alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl,aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl,alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R² substituentsinclude methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl,cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃, CH₂CH₂CH₂OH,CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂, CH₂CH₂CH₂NHCOOC(CH₃)₃,CONHCH (CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃, CONHCH₂Ph,CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂,CO(3-methoxymethylpyrrolidin-1-yl), CONH (3-tolyl), CONH (4-tolyl),CONHCH₃, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH,CONH₂, and CO(piperidin-1-yl). A more preferred R² group for formula IXcompounds is hydrogen.

An embodiment that is particularly useful for treating GSK3-mediateddiseases relates to compounds of formula X wherein ring A is apyrimidine ring:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

R¹ is selected from -halo, —CN, —NO₂,T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² is —R or —T—W—R⁶;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O) N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶.

Compounds of formula X are structurally similar to compounds of formulaII except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y) and Ring C groups offormula X are as described above for the formula II compounds. Preferredformula X compounds have one or more, and more preferably all, of thefeatures selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 0-2 ring nitrogens;

(c) R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶; and

(d) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group.

More preferred compounds of formula X have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formedby R^(x) and R^(y) is optionally substituted with —R, halo, —OR,—C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

(c) R¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group,phenyl, or —CN;

(d) R² is hydrogen or a substituted or unsubstituted group selected fromaryl or a C₁₋₆ aliphatic group; and

(e) each R⁵ is independently selected from -halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R.

Even more preferred compounds of formula X have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring;

(b) R^(x) is hydrogen or methyl and R^(y) is methyl, methoxymethyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionallysubstituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, orphenyl, or R^(x) and R^(y) are taken together with their interveningatoms to form an optionally substituted benzo ring or a 6-memberedcarbocyclo ring;

(c) R¹ is -halo, a C₁₋₄ aliphatic group optionally substituted withhalogen, or —CN;

(d) R² is hydrogen or a C₁₋₆ aliphatic group; and

(e) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃, —NH₂,—NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic).

Another embodiment of this invention relates to compounds of formula XI:

or a pharmaceutically acceptable derivate or prodrug thereof, wherein:

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴ provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R^(x) and R^(y) are taken together with their intervening atoms to forma fused benzo ring or 5-8 membered carbocyclo ring, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² is —R or —T—W—R⁶;

R³ is selected from —R, -halo, ═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,N(R⁶)N(R⁶) —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formulaIII except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y), and Ring D groups offormula XI are as described above for the formula III compounds.Preferred formula XI compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from a phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) and R^(y) are taken together with their intervening atoms toform an optionally substituted benzo ring or 5-7 membered carbocycloring; and

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group.

More preferred compounds of formula XI have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or 5-7 membered carbocyclo ring, wherein said ringformed by R^(x) and R^(y) is optionally substituted with —R, oxo, halo,—OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl or a C₁₋₆ aliphatic group; and

(d) each R⁵ is independently selected from halo, oxo, CN, NO₂, —N(R⁴)₂,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —SR, —OR, —C(O)R,or a substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

Even more preferred compounds of formula XI have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a benzo ring or 6-membered carbocyclo ring, wherein said ringformed by R^(x) and R^(y) is optionally substituted with halo, CN, oxo,C₁₋₆ alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl,mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

(c) R² is hydrogen or a C₁₋₆ aliphatic group.

Another embodiment of this invention relates to compounds of formulaXII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring is optionally and independentlysubstituted by T—R³, and any substitutable nitrogen on said ring issubstituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² is —R or —T—W—R⁶;

R³ is selected from —R, -halo,═O, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ o aryl, aheteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having5-10 ring atoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,N(R⁶)N(R⁶) —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclylring or heteroaryl.

Compounds of formula XII are structurally similar to compounds offormula IV except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y), and Ring D groups offormula XII are as described above for the formula IV compounds.Preferred formula XII compounds have one or more, and more preferablyall, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from a phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl,morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 1-2 ring heteroatoms; and

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group.

More preferred compounds of formula XII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring D is an optionally substituted ring selected from phenyl,pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma 5-7 membered unsaturated or partially unsaturated ring having 1-2 ringnitrogens, wherein said ring is optionally substituted with —R, halo,oxo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR,—N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴) SO₂N(R⁴)₂, —N(R⁴) SO₂R, or—OC(═O)N(R⁴)₂;

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl or a C₁₋₆ aliphatic group; and

(d) each R⁵ is independently selected from halo, oxo, CN, NO₂, —N(R⁴)₂,—CO₂R, —CONH(R⁴), —N(R⁴) COR, —SO₂N(R⁴)₂, —N(R⁴) SO₂R, —SR, —OR, —C(O)R,or a substituted or unsubstituted group selected from 5-6 memberedheterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic.

Even more preferred compounds of formula XII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) and R^(y) are taken together with their intervening atoms toform a 6-membered unsaturated or partially unsaturated ring having 1-2ring nitrogens, optionally substituted with halo, CN, oxo, C₁₋₆ alkyl,C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl, mono- ordialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(b) each R⁵ is independently selected from -halo, —CN, -oxo, —SR, —OR,—N(R⁴)₂, —C(O)R, or a substituted or unsubstituted group selected from5-6 membered heterocyclyl, C₆₋₁₀ aryl, or C₁₋₆ aliphatic; and

(c) R² is hydrogen or a C₁₋₆ aliphatic group.

Another embodiment of this invention relates to compounds of formulaXIII:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z¹ is nitrogen, CR^(a), or CH, and Z² is nitrogen or CH; provided thatone of Z¹ and Z² is nitrogen;

G is Ring C or Ring D;

Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or twoortho substituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸;

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ringselected from aryl, heteroaryl, heterocyclyl or carbocyclyl, saidheteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selectedfrom nitrogen, oxygen or sulfur, wherein Ring D is substituted at anysubstitutable ring carbon by oxo or —R⁵, and at any substitutable ringnitrogen by —R⁴, provided that when Ring D is a six-membered aryl orheteroaryl ring, —R⁵ is hydrogen at each ortho carbon position of RingD;

R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶, phenyl, 5-6 memberedheteroaryl ring, 5-6 membered heterocyclyl ring, or C₁₋₆ aliphaticgroup, said phenyl, heteroaryl, and heterocyclyl rings each optionallysubstituted by up to three groups independently selected from halo, oxo,or —R⁸, said C₁₋₆ aliphatic group optionally substituted with halo,cyano, nitro, or oxygen, or R¹ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

R^(x) and R^(y) are independently selected from T—R³, or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴;

T is a valence bond or a C₁₋₄ alkylidene chain;

R² is —R or —T—W—R⁶;

R³ is selected from —R, -halo, —OR, —C(═O)R, —CO₂R, —COCOR, —COCH₂COR,—NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂,—OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂ (optionallysubstituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the samenitrogen are taken together to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁵ is independently selected from —R, halo, —OR, —C(═O)R, —CO₂R,—COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂,—OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C;

V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O) O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

each R⁶ is independently selected from hydrogen, an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring;

each R⁸ is independently selected from an optionally substituted C₁₋₄aliphatic group, —OR⁶, —SR⁶, —COR⁶, —SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN,—NO₂, —CON(R⁶)₂, or —CO₂R⁶; and

R^(a) is selected from halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂ —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R,—OC(═O)N(R⁴)₂, or an optionally substituted group selected from C₁₋₆aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, or aheterocyclyl ring having 5-10 ring atoms.

Compounds of formula XIII may be represented by specifying Z¹ and z² asshown below:

Compounds of formula XIII are structurally similar to compounds offormula V except for the replacement of the pyrazole ring moiety by thetriazole ring moiety. Preferred R², R^(x), R^(y), R^(a), and Ring Ggroups of formula XIII are as described above for the formula Vcompounds. Preferred formula XIII compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is selected from anaphthyl, quinolinyl or isoquinolinyl ring, and R¹ is -halo, anoptionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶, —CN,—SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; or Ring D is an optionally substituted ring selected from aphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl,azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl,2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

(b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y) is T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form anoptionally substituted 5-7 membered unsaturated or partially unsaturatedring having 0-2 ring nitrogens; and

(c) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, heteroaryl, or a C₁₋₆ aliphatic group.

More preferred compounds of formula XIII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆ aliphatic group, phenyl,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl,quinolinyl, or naphthyl;

(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formedby R^(x) and R^(y) is optionally substituted with —R, halo, —OR,—C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

(C) R² is hydrogen or a substituted or unsubstituted group selected fromaryl, or a C₁₋₆ aliphatic group; and

(d) each R⁵ is independently selected from -halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, or —N(R⁴)SO₂R, and, when Ring G isRing D, Ring D is substituted by oxo or R⁵.

Even more preferred compounds of formula XIII have one or more, and morepreferably all, of the features selected from the group consisting of:

(a) R^(x) is hydrogen or methyl and R^(y) is methyl, methoxymethyl,ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionallysubstituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, orphenyl, or R^(x) and R^(y) are taken together with their interveningatoms to form a benzo ring or a 6-membered carbocyclo ring wherein saidring formed by R^(x) and R^(y) is optionally substituted with halo, CN,oxo, Cls alkyl, C₁₋₆ alkoxy, (C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyl)sulfonyl,mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- ordialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

(b) Ring C is a phenyl or pyridinyl ring, optionally substituted by —R⁵,wherein when Ring C and two adjacent substituents thereon form abicyclic ring system, the bicyclic ring system is a naphthyl ring, andR¹ is -halo, a C₁₋₄ aliphatic group optionally substituted with halogen,or —CN; or Ring D is an optionally substituted ring selected fromphenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,isoquinolinyl, quinolinyl, or naphthyl;

(c) R² is hydrogen or a C₁₋₆ aliphatic group; and

(d) each R⁵ is independently selected from —Cl, —F, —CN, —CF₃, —NH₂,—NH(C₁₋₄ aliphatic), —N(C₁-₄ aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄aliphatic, and —CO₂(C₁₋₄ aliphatic), and when Ring G is Ring D, Ring Dis substituted by oxo or R⁵.

Representative compounds of formula IX are shown below in Table 8.

TABLE 8

IX-1

IX-2

IX-3

IX-4

IX-5

IX-6

IX-7

IX-8

IX-9

IX-10

IX-11

IX-12

IX-13

IX-14

IX-15

IX-16

IX-17

IX-18

IX-19

IX-20

IX-21

IX-22

IX-23

IX-24

IX-25

IX-26

IX-27

IX-28

IX-29

IX-30

IX-31

IX-32

IX-33

IX-34

IX-35

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In another embodiment, this invention provides a composition comprisinga compound of formula IX and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3activity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IX.

Another aspect relates to a method of treating a disease that isalleviated by treatment with a GSK-3 inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IX.

Another aspect relates to a method of enhancing glycogen synthesisand/or lowering blood levels of glucose in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a composition comprising a compound of formula IX. This methodis especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production ofhyperphosphorylated Tau protein in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acomposition comprising a compound of formula IX. This method isespecially useful in halting or slowing the progression of Alzheimer'sdisease.

Another aspect relates to a method of inhibiting the phosphorylation ofβ-catenin in a patient in need thereof, comprising administering to saidpatient a therapeutically effective amount of a composition comprising acompound of formula IX. This method is especially useful for treatingschizophrenia.

One aspect of this invention relates to a method of inhibiting Auroraactivity in a patient, comprising administering to the patient atherapeutically effective amount of a composition comprising a compoundof formula IX.

Another aspect relates to a method of treating a disease that isalleviated by treatment with an Aurora inhibitor, said method comprisingthe step of administering to a patient in need of such a treatment atherapeutically effective amount of a composition comprising a compoundof formula IX. This method is especially useful for treating cancer,such as colon, ovarian, and breast cancer.

Another method relates to inhibiting GSK-3 or Aurora activity in abiological sample, which method comprises contacting the biologicalsample with the GSK-3 or Aurora inhibitor of formula IX, or apharmaceutical composition thereof, in an amount effective to inhibitGSK-3 or Aurora.

Each of the aforementioned compositions and methods directed to theinhibition of GSK-3 or Aurora, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIX, as described above.

The compounds of this invention may be prepared as illustrated by theSynthetic Methods below, by the Synthetic Examples described herein andby general methods known to those skilled in the art.

General Synthetic Methods

The general synthetic methods below provide a series of general reactionroutes that were used to prepare compounds of this invention. MethodsA-F below are particularly useful for preparing formula II compounds. Inmost cases, Ring C is drawn as a phenyl ring bearing an ortho R¹substituent. However, it will be apparent to one skilled in the art thatcompounds having other Ring C groups may be obtained in a similarmanner. Methods analogous to methods A-F are also useful for preparingother compounds of this invention. Methods F-I below are particularyuseful for preparing compounds of formula III or IV.

Method A is a general route for the preparation of compounds whereinring C is an aryl or heteroaryl ring. Preparation of the startingdichloropyrimidine 1 may be achieved in a manner similar to thatdescribed in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124. The chlorine inposition 4 of intermediate 1 may be replaced by an aminopyrazole oraminoindazole to provide intermediate 2 in a manner similar to thatdescribed in J. Med. Chem., 38, 3547-3557 (1995). Ring C is thenintroduced using a boronic ester under palladium catalysis (seeTetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by thefollowing procedure.

A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl₃(60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) is heatedunder reflux for 2 h. Excess POCl₃ is evaporated under vacuum, theresidue is poured into ice, and the precipitate is collected byfiltration. The crude solid 2,4-dichloroquinazoline product may be usedwithout further purification.

To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) inanhydrous ethanol (150 mL) is added 5-methyl-1H-pyrazol-3-yl amine (3.2g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, andthe resulting precipitate is collected by filtration, washed withethanol, and dried under vacuum to afford(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine.

To a solution of(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19mmol) in DMF (1.0 mL) is added the desired arylboronic acid (0.38 mmol),2M Na2CO3 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Undernitrogen, PdCl₂(dppf) (0.011 mmol) is added in one portion. The reactionmixture is then heated at 80° C. for 5 to 10 hours, cooled to roomtemperature, and poured into water (2 mL). The resulting precipitate iscollected by filtration, washed with water, and purified by HPLC.

Methods B through F describe routes where the pyrazole ring system isintroduced after Ring C and the pyrimidine ring portion are firstconstructed. A versatile intermediate is the 4-chloropyrimidine 4, whichis readily obtained from pyrimidinone 3 as shown in Method B(i). Thisreaction sequence is generally applicable for a variety of Ring C groupsincluding aliphatic, aryl, heteroaryl, or heterocyclyl. See J. Med.Chem., 38, 3547-3557 (1995).

For quinazoline ring systems (where R^(x) and R^(y) are taken togetherto form a benzo ring), the useful intermediate 6 may be obtained bycondensing an anthranilic acid or its derivative with a benzamidine asshown in Method B(ii) or by condensing a benzoylchloride with ananthranilamide as shown in Method B(iii). Many substituted anthranilicacid, anthranilamide, benzamidine and benzoylchloride starting materialsmay be obtained by known methods. See Aust. J. Chem., 38, 467-474 and J.Med. Chem., 38, 3547-3557 (1995). Method B(iii) is illustrated by thefollowing procedure.

To a solution of anthranilamide (33 mmol) in THF and CH₂Cl₂ (1:1, 70 mL)is added the desired benzoylchloride (33 mmol), and triethylamine (99mmol) at room temperature. The mixture is stirred for about 14 hours.The resulting precipitate is collected by filtration, washed with CH₂Cl₂and water, and dried under vacuum. The crude 2-benzoylaminobenzamide maybe used directly for the next step without further purification.

To a solution of the above crude product (13 mmol) in ethanol (50 mL) isadded NaOEt (26 mmol) at room temperature. The mixture is heated underreflux for 48 to 96 h. The solvent is evaporated and the residue isneutralized using concentrated HCl to pH 7. The product is thencollected by filtration and dried under vacuum to provide2-phenyl-3H-quinazolin-4-one that may be used without furtherpurification.

To a suspension of the above product (12 mmol) in POCl₃ (120 mmol) isadded tri-n-propylamine (24 mmol) The mixture is heated under reflux for1 h. After removal of the excess POCl₃ by evaporation, the residue isdissolved in ethyl acetate, and washed with 1N NaOH (twice) and water(twice). The organic layer is dried over MgSO₄, the solvent isevaporated under vacuum, and the crude product is purified by flashchromatography (eluting with 10% of ethyl actetate in hexanes) to give4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF (or THF,ethanol) (1 mL) is added the desired aminopyrazole or aminoindazole(0.32 mmol). The mixture is heated in DMF (or THF under reflux) at 100to 110° C. for 16 h (or in ethanol at 130-160° C. for 16 hours) and thenpoured into water (2 mL). The precipitate is collected by filtration andpurified by HPLC.

Methods C and D(i) above employ β-ketoesters 8 and 10, respectively, aspyrimidinone precursors. The substitution pattern of the R^(x) and R^(y)groups on the pyrimidinone ring will be reversed if a chlorocrotonate 11(Synth. Comm, (1986), 997-1002), instead of the correspondingβ-ketoester 10, is condensed with the desired benzamidine. These methodsare illustrated by the following general procedure.

To a solution of a β-ketoester (5.2 mmol) and amidinium chloride (5.7mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). The mixtureis heated under reflux for 7-14 hours. After evaporation the resultingresidue is dissolved in water, acidified with concentrated HCl to pH 6,and then filtered to obtain a solid product 2-aryl-3H-pyrimidin-4-one(yield 75-87%), which may be purified by flash column chromatography ifneeded. To this pyrimidinone (3.7 mmol) is added POCl₃ (4 mL) and n-Pr₃N(1.4 mL). The mixture is heated under reflux for 1 hour. Afterevaporation of the excess POCl₃, the residue is dissolved in ethylacetate, washed with 1N NaOH solution (three times) and NaHCO₃ (once),and dried over MgSO₄. The solvent is removed under vacuum and theresidue is purified by flash column chromatography eluting with 10% ofethyl acetate in hexanes to give 2-aryl-4-chloro-pyrimidine as a paleyellow syrup. This crude product may be treated with a 3-aminopyrazoleor 3-aminoindazole as described above.

Method D(ii) above shows a general route for the preparation of thepresent compounds, such as compound 40, wherein R^(y) is N(R⁴)₂. See IlFarmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group isexemplified here using morpholine. This method is illustrated by thefollowing procedure.

To a solution of 2-methylmalonic acid diethyl ester (5 mmol) and sodiumethoxide (15 mmol) is added the appropriate amidine salt (5 mmol) inethanol (10 mL) and the reaction heated at reflux for 2-24 hours. Theresidue is dissolved in water and acidified with 2N HCl. The resultingprecipitate is filtered off and further purified by flash chromatography(yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) isadded POCl₃ (32 mmol) and tri-n-propylamine (6.4 mmol) and the reactionrefluxed is for 1 h. After evaporation of excess POCl₃, the residue isdissolved in ethyl acetate, basified with 1N NaOH, separated and theaqueous phase twice more extracted with ethyl acetate. The combinedorganics are dried (sodium sulfate) and evaporated. Purification byflash chromatography provides the dichloropyrimidine (38) as a yellowoil in 23% yield.

A solution of 38 (0.33 mmol) in methanol (5 mL) is treated with anamine, exemplified here using morpholine (0.64 mmol) and refluxed 1hour. After evaporation of solvent, the residue is purified by flashchromatography to provide the mono-chloropyrimidine 39 as a colorlessoil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may be treated with a3-aminopyrazole or 3-aminoindazole compound in a manner substantiallysimilar those described above in Methods A and B.

As shown by Method E, an acyl isocyanate 12 may be condensed with anenamine to provide pyrimidinone 9 (J. Org. Chem (1993), 58, 414-418;J.Med.Chem., (1992), 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214).This method is illustrated by the following general procedure.

The enamine is prepared according to W. White, et al, J. Org Chem.(1967), 32, 213-214. The acyl isocyanate is prepared according to GBradley, et al, J Med. Chem. (1992), 35, 1515-1520. The couplingreaction then follows the procedure of S Kawamura, et al, J. Org. Chem,(1993), 58, 414-418. To the enamine (10 mmol) in tetrahydrofuran (30 mL)at 0° C. under nitrogen is added dropwise over 5 min a solution of acylisocyanate (10 mmol) in tetrahydrofuran (5 mL). After stirring for 0.5h, acetic acid (30 mL) is added, followed by ammonium acetate (50 mmol).The mixture is refluxed for 2 h with continuous removal oftetrahydrofuran. The reaction is cooled to room temperature and ispoured into water (100 mL). The precipitate is filtered, washed withwater and ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

Method F shows a general route for the preparation of the presentcompounds wherein R^(x) and R^(y) are taken together to form a 5-8membered partially unsaturated saturated or unsaturated ring having 1-3heteroatoms. The condensation of a 2-amino-carboxylic acid, such as2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone14. Treatment of 14 with ammonium hydroxide will furnish the benzamide15 which may be cyclized to a2-(substituted)-pyrido[2,3-d][1,3]pyrimidin-4-one 16. This method isillustrated by the following procedure.

2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mmol) is addeddropwise to a solution of 2-aminonicotinic acid (2.04 g, 14.76 mmol) in20 ml of pyridine. The reaction mixture is heated at 158 C for 30 minthen cooled to room temperature. The reaction is poured into 200 ml ofwater and an oil forms which solidifies upon stirring. The solid iscollected by vacuum filtration and washed with water and diethyl ether.The product is dried to give2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.56 g, 60%yield) which may be used in the next step without further purification.

2-(2-Trifluoromethyl-phenyl)-pyrido[2,3-d][1,3]oxazin-4-one (2.51 g) isstirred in 30% ammonium hydroxide (25 ml) at room temperature overnight.The resulting precipitate is filtered and rinsed with water and diethylether. The precipitate is dried under vacuum at 50 C overnight to give2-(2-trifluoromethyl-benzoylamino)-nicotinamide (850 mg, 33% yield)

2-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800 mg, 2.6 mmol) isdissolved in 10 ml of ethanol. Potassium ethoxide (435 mg, 5.2 mmol) isadded to the solution which is heated to reflux for 16 h. The reactionmixture is evaporated in vacuo to afford a gummy residue that isdissolved in water and acidified with 10% sodium hydrogen sulfate to pH7. The resulting precipitate is filtered and dried under vacuum at 50 Cto give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3-d]pyrimidin-4-one.

Method G

Method G is analogous to Method B(i) above. This method is illustratedby the following general procedure.

2-(3,4-Dichloro-phenyl)-3H-quinazolin-4-one (1 g, 3.43 mmol) issuspended in phosphorus oxychloride (4 mL) and the reaction mixture wasstirred at 110° C. for 3 hours. The solvents are then evaporated and theresidue is treated carefully with an ice cold aqueous saturated solutionof NaHCO₃. The solid is collected by filtration and washed with ether togive 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline as a white solid (993mg, 93%).

To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400 mg, 1.29 mmol) inTHF (30 mL) is added 3-amino-5-methyl pyrazole (396 mg, 2.58 mmol) andthe reaction mixture is heated at 65° C. overnight. The solvents arethen evaporated and the residue triturated with ethyl acetate, filteredand washed with a minimum amount of ethanol to give[2-(3,4-dichlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amineas a white solid (311 mg 65%): mp 274° C.; ¹H NMR (DMSO) δ 2.34 (3H, s),6.69 (1H, s), 7.60 (1H, m), 7.84 (1H, d), 7.96 (2H, d), 8.39 (1H, dd),8.60 (1H, d), 8.65 (1H, d), 10.51 (1H, s), 12.30 (1H, s); IR (solid)1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5(M+H)⁺.

The THF solvent used in the previous step may be replaced by otherorganic solvents such as ethanol, N,N-dimethylformamide, or dioxane.

Method H shows routes in which a Ring D aryl group bearing a halogen (Xis Br or I) may be converted to other formula III compounds. Method H(i)shows a phenylboronic acid coupling to Ring D to provide compound 18 andMethod H(ii) shows an acetylene coupling to provide compound 19.Substituent X in compound 17 may be bromine or iodine. These methods areillustrated by the following procedures.

Method H(i). To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) inTHF/water (1/1, 4 mL) is added Na₂CO₃ (219 mg, 2.06, mmol),triphenylphosphine (9 mg, 1/15 mol %) and palladium acetate (1 mg, 1/135mol %). The mixture is heated at 80° C. overnight, the solvents areevaporated and the residue is purified by flash chromatography (gradientof CH₂Cl₂/MeOH) to give(2-biphenyl-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as ayellow solid (99 mg, 51%): ¹H NMR (DMSO) 67 2.37 (3H, s), 6.82 (1H, s),7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d), 10.42(1H, s), 12.27 (1H, s); MS 378.2 (M+H)⁺

Method H(ii). To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol) inDMF (2 mL) is added CuI (1.1 mg, 1/50 mol %), Pd(PPh₃)₂Cl₂ (4.2 mg, 1/50mol %) and triethylamine (121 mg, 0.36 mmol). The mixture is heated at120° C. overnight and the solvent is evaporated. The residue istriturated in ethyl acetate and the precipitate is collected byfiltration.

To the above precipitate suspended in THF (3 mL) is addedtetrabutylammonium fluoride (1M in THF, 1.1 eq). The reaction mixture isstirred at room temperature for two hours and the solvent is evaporated.The residue is purified by flash chromatography (gradient ofCH₂Cl₂/MeOH) to give[2-(4-ethynylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amineas a white solid (68 mg, 70%): ¹H NMR (DMSO) 67 2.34 (3H, s), 4.36(1H_(,) s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47(2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M+H)⁺

Method I above shows a general route for the preparation of the presentcompounds wherein ring D is a heteroaryl or heterocyclyl ring directlyattached to the pyrimidine 2-position via a nitrogen atom. Displacementof the 2-chloro group, exemplified here using piperidine, may be carriedout in a manner similar to that described in J. Med. Chem., 38,2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method isillustrated by the following procedure.

To a solution of (2-chloro-quinazolin-4-yl)-(1H-indazol-3-yl)-amine (1equivalent, 0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml) is added thedesired amine (3 equivalents). The resulting mixture is maintained at100° C. for 6 h and then purified by reverse-phase HPLC.

Method J above shows the preparation of compounds of formula V via thedisplacement of a chloro group from an appropriately substituted pyridylring. Method J(i) is a route for preparing compounds of formula Va (seeIndian J. Chem. Sect.B, 35, 8, 1996, 871-873). Method J(ii) is a routefor preparing compounds of formula Vb (see Bioorg. Med. Chem.,6, 12,1998, 2449-2458). For convenience, the chloropyridines 21 and 23 areshown with a phenyl substituent corresponding to Ring D of formula V. Itwould be apparent to one skilled in the art that Method J is also usefulfor preparing compounds of formula V wherein Ring D is heteroaryl,heterocyclyl, carbocyclyl or other aryl rings. Method J is illustratedby the following procedures.

Method J(i). (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine.To 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983, 121-128)(0.53 g,2.21 mmol) in diphenylether (5 mL) was added 3-amino-5-methylpyrazole(0.43 g, 4.42 mmol) and the mixture was heated at 200° C. overnight withstirring. To the cooled mixture was added petroleum ether (20 mL) andthe resulting crude precipitate was filtered and further washed withpetroleum ether. The crude solid was purified by flash chromatography(SiO₂, gradient DCM-MeOH) to give the title compound as a white solid:mp 242-244° C.; ¹H NMR (DMSO) 67 2.27(3H, s), 6.02(1H, s), 7.47(2H, d),7.53-7.40(2H, br m), 7.67(1H, m), 7.92(1H, m), 8.09(2H, d), 8.48(2H, m),9.20(1H, s), 12.17(1H, br s); IR (solid) 1584, 1559, 1554, 1483, 1447,1430, 1389; MS 301.2 (M+H)⁺

Method J(ii).(5-Methyl-2H-pyrazol-3-yl)-(3-phenyl-isoquinolin-1-yl)-amine. To1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983, 121-128)(0.33 g,1.37 mmol) in dry DMF (5 mL) was added 3-amino-5-methylpyrazole (0.27 g,2.74 mmol) and potassium carbonate (0.57 g, 4.13 mmol)and the mixturewas heated under reflux for 6 hours. The mixture was cooled and the bulkof DMF was evaporated. The residue was extracted twice with ethylacetate and the combined organic layers were washed with brine, dried(MgSO₄), filtered and concentrated. The crude was purified by flashchromatography (SiO₂, gradient DCM-MeOH) to give the title compound as acolourless oil; ¹H NMR (MeOD) 67 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H,m), 7.52(2H, m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m),8.29(1H, s), 8.54 (1H, d); MS 301.2 (M+H)⁺

Method K shows a route for the preparation of compounds of formula VI. Aversatile starting material is 2,4,6-trichloro-[1,3,5]triazine 25 inwhich the chlorine substituents may be sequentially displaced. Thedisplacement of one of the chlorines by an aryl Grignard reagent or anaryl boronic acid is described in PCT patent application WO 01/25220 andHelv. Chim. Acta, 33, 1365 (1950). The displacement of one of thechlorines by a heteroaryl ring is described in WO 01/25220; J. Het.Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975). These reactionsprovide a 2,4-dichloro-(6-substituted)[1,3,5]triazine 26 that is auseful intermediate for the preparation of compounds of formula VI.Alternatively, intermediate 26 may be obtained by constructing thetriazine ring by known methods. See U.S. Pat. No. 2,832,779; and U.S.Pat. No. 2,691,020 together with J. Am. Chem. Soc. 60, 1656 (1938). Inturn, one of the chlorines of 26 may be displaced as described above toprovide 2-chloro-(4,6-disubstituted)[1,3,5]triazine 27. The treatment of27 with an appropriate aminopyrazole provides the desired compound offormula VI.

Method L shows a route for preparing compounds of formula VII. Forillustration purposes the trifluoromethylchalcone 28 is used as astarting material; however, it would be apparent to one skilled in theart that other rings may be used in place of the trifluoromethylphenyland phenyl rings of compound 28. Substituted chalcones may be preparedby known methods, for example as described in the Indian J. Chemistry,32B, 449 (1993). Condensation of a chalcone with urea provides thepyrimidinone 29, which may be treated with POCl₃ to give thechloropyrimidine 30. See J. Chem. Eng. Data, 30(4) 512 (1985) and Egypt.J. Chem., 37(3), 283 (1994). In an alternative approach to compound 30,one of the aryl rings attached to the pyrimidine is introduced bydisplacement of of the 4-chloro group of2,4-dichloro-(6-aryl)-pyrimidine by an aryl boronic acid using apalladium catalyst such as (Ph₃P)₄Pd in the presence of a base such assodium carbonate as described in Bioorg. Med. Lett., 9(7), 1057 (1999).Displacement of the chlorine of compound 30 by an appropriateaminopyrazole provides compounds of this invention, such as 31. The laststep of this method is illustrated by the following procedure.

[4-(4-Methylpiperidin-1-yl)-pyrimidin-2-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine(prepared using a procedure similar to the one reported in Eur. J. Med.Chem., 26(7) 729(1991))(222 mg, 1.05 mmol) in BuOH (5 mL) was added3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) and the reactionmixture was then heated under reflux overnight. The solvent wasevaporated and the residue dissolved in a mixture ethanol/water (1/3, 4mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixturewas stirred at room temperature for 2 hours. The resulting suspensionwas filtered, washed with water twice and rinsed with ether twice togive the title compound as a white solid (143 mg, 50%): mp 193-195° C.;¹H NMR (DMSO) 67 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s),2.83 (2H, t), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s),11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322,1246; MS 273.3(M+H)⁺.

Method M provides routes for obtaining compounds of formula VIII. Ageneral procedure for displacing the chlorine of a4-chloro-6-substituted-pyridazine, 32, with an appropriately substitutedpyrazole to provide Vllla is described in J. Het. Chem., 20, 1473(1983). Analogous reactions may be carried out as follows: (a) with3-chloro-5-substituted-pyridazine, 33, to provide VIIIb is described inJ. Med. Chem., 41(3), 311 (1998); (b) with5-chloro-3-substituted-[1,2,4] triazine, 34, to provide VIIIc isdescribed in Heterocycles, 26(12), 3259 (1987); and (c) with3-chloro-5-substituted-[1,2,4]triazine, 35, to provide VIIId isdescribed in Pol. J. Chem., 57, 7, (1983); Indian J. Chem. Sect. B, 26,496 (1987); and Agric. Biol. Chem., 54(12), 3367 (1990). An alternativeprocedure to compounds of formula VIIlc is described in Indian J. Chem.Sect. B, 29(5), 435 (1990).

Compounds of formula IX are prepared by methods substantially similar tothose described above for the pyrazole-containing compounds of formulaI. Methods A-J may be used to prepare the triazole-containing compoundsof formula IX by replacing the amino-pyrazole compound with anamino-triazole compound. Such methods are specifically exemplified bySynthetic Examples 415-422 set forth below. The amino-triazoleintermediate may be obtained by methods described in J. Org. Chem. USSR,27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing theprotein kinase inhibitors of this invention are new. Accordingly,another aspect of this invention relates to a 3-aminoindazole compoundof formula A:

where R¹⁰ is one to three substituents that are each independentlyselected from fluoro, bromo, C₁₋₆ haloalkyl, nitro, or 1-pyrrolyl.Examples of such compounds include the following:

Another aspect of this invention relates to a 4-chloropyrimidinecompound of formula B:

wherein R^(x) and R^(y) are as defined above; R¹ is selected from Cl, F,CF₃, CN, or NO₂; and is one to three substituents that are eachindependently selected from H, Cl, F, CF₃, NO₂, or CN; provided that R¹and R⁵ are not simultaneously Cl. Examples of compounds of formula B areshown below:

Another aspect of this invention relates to compounds of formula C:

wherein R^(x), R^(y), R², and R^(2′) are as defined above. Examples ofcompounds of formula C are shown below:

Yet another aspect of this invention relates to compounds of formula D:

where R⁵, R^(x) and R^(y) are as defined above. Examples of formula Dcompounds and other useful pyrimidinone intermediates are shown below:

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

The following HPLC methods were used in the analysis of the compounds asspecified in the Synthetic Examples set forth below. As used herein, theterm “R_(t)” refers to the retention time observed for the compoundusing the HPLC method specified.

HPLC-Method A

Column: C18, 3 μm, 2.1×50 mm, “Lighting” by Jones Chromatography.

Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100%acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100%acetonitrile for 1.4 min and return to initial conditions. Total runtime 7.0 min. Flow rate: 0.8 mL/min.

HPLC-Method B

Column: C18, 5 μm, 4.6×150 mm “Dynamax” by Rainin

Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100%acetonitrile (containing 0.1% TFA) over 20 min, hold at 100%acetonitrile for 7.0 min and return to initial conditions. Total runtime 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C

Column: Cyano, 5 um, 4.6×150 mm “Microsorb” by Varian.

Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA) over 20min, hold for 8.0 min and return to initial conditions. Total run time30 min. Flow rate: 1.0 mL/min.

HPLC-Method D

Column: Waters (YMC)ODS-AQ 2.0×50 mm, S5, 120A.

Gradient: 90% water (0.2% Formic acid), 10% acetonitrile (containing0.1% Formic acid) to 10% water (0.1% formic acid), 90% acetonitrile(containing 0.1% formic acid) over 5.0 min, hold for 0.8 min and returnto initial conditions. Total run time 7.0 min.

Flow rate: 1.0 mL/min.

HPLC-Method E

Column: 50×2.0 mm Hypersil C18 BDS; 5 μm

Gradient: elution 100% water (0.1% TFA), to 5% water (0.1% TFA), 95%acetonitrile (containing 0.1% TFA) over 2.1 min, returning to initialconditions after 2.3 min.

Flow rate: 1 mL/min.

Example 1[2-(2-Clorophenyl)-5,6-dimethylpyrimidin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-1)

¹HNMR (500 MHz, DMSO-d6) δ 110.4 (s, br, 1H), 7.74 (m, 2H), 7.68 (m,1H), 7.60 (m, 1H), 6.39 (s, 1H), 2.52 (s, 3H), 2.30 (s, 3H), 2.22 (s,3H); MS 314.1 (M+H).

Example 2[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(1H-indazol-3-yl)-amine(11-2)

Prepared in 30% yield. ¹HNMR (500 MHz, DMSO-d6) 67 1.72 (m, 4H), 1.91(m, 2H), 3.02 (m, 4H), 7.05 (t, 1H), 7.33 (t, 1H), 7.39 (m, 1H), 7.47(d, 1H), 7.55 (m, 3H), 7.59 (d, 1H), 10.4 (m, 1H), 13.11 (br. s, 1H);EI-MS 390.2 (M+H); HPLC-Method A, R_(t) 2.99 min.

Example 3(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,28-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine(II-3)

Compound II-18 (90 mg, 0.17 mmol) was treated with an equal weight ofPd/C (10%) in 4.4% formic acid in MeOH at room temperature for 14 h. Themixture was filtered through celite, the filtrate was evaporated, andcrude product was purified by HPLC to provide 18 mg (24%) of the desiredproduct as pale yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ 12.9 (s, 1H),9.51 (s, 1H), 9.26 (s, 2H), 7.72 (d, 1H), 7.63 (t, 1H), 7.58 (t, 1H),7.49 (m, 2H), 7.21 (td, 1H), 7.15 (dd, 1H), 4.24 (s, 2H), 3.56 (m, 2H),2.95 (m, 2H) ppm. MS (ES+): m/e=429.22 (M+H); HPLC-Method A, R_(t) 2.88min.

Example 4[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-4)

Prepared in 52% yield to afford a white solid. ¹HNMR (500 MHz, DMSO-d6)δ 1.72 (m, 4H), 1.92 (m, 2H), 3.00 (m, 4H), 7.02 (td, 1H), 7.20 (dd,1H), 7.40 (m, 1H), 7.42 (d, 1H), 7.52 (m, 3H), 10.5 (m, 1H), 13.50 (br.s, 1H); EI-MS 408.2 (M+H); HPLC-Method A, R_(t) 3.00 min.

Example 5[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-5)

Prepared in 51% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.71 (m, 4H), 1.91 (m,2H), 3.01 (m, 4H), 7.24 (td, 1H), 7.41 (m, 2H), 7.54 (m, 4H), 10.5 (m,1H), 13.1 (br. s, 1H); EI-MS 408.2 (M+H); HPLC-Method A, R_(t) 3.05 min.

Example 6[2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-6)

Prepared according to Method C in 72% yield. ¹HNMR (500 MHz, DMSO-d6) 671.72 (m, 4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.31 (m, 2H), 7.41 (m, 1H),7.54 (m, 3H), 10.5 (m, 1H), 13.6 (br. s, 1H); EI-MS 426.2 (M+H);HPLC-Method A, R_(t) 3.21 min.

Example 7(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-7)

Prepared in 62% yield. ¹HNMR (500 MHz, DMSO-d6) δ13.5 (s, br, 1H), 10.1(s, br, 1H), 7.75 (m, 4H), 7.33 (d, 1H), 7.17 (dd, 1H), 7.00 (td, 1H),2.80 (m, 2H), 2.71 (m, 2H), 1.89 (br, 4H) ppm; LC-MS (ES+) 428.44 (M+H),(ES−) 426.43 (M−H); HPLC-Method A, R_(t) 3.02 min.

Example 8(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-8)

Prepared in 53% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.1 (s, 1H), 10.2 (s,br, 1H), 7.75 (m, 4H), 7.50 (dd, 1H), 7.27 (dd, 1H), 7.21 (td, 1H), 2.80(m, 2H), 2.72 (m, 2H), 1.88 (m, 4H) ppm; MS (ES+) 428.43 (M+H), (ES−)426.43 (M−H); HPLC-Method A, R_(t) 3.01 min.

Example 9(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-9)

Prepared in 37% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.7 (s, 1H), 10.2 (s,br, 1H), 7.80 (d, 1H), 7.76 (t, 1H), 7.69 (m, 2H), 7.31 (t, 1H), 7.18(d, 1H), 2.81 (t, br, 2H), 2.72 (t, br, 2H), 1.90 (m, 4H) ppm; MS (ES+)446.42 (M+H), (ES−) 444.37 (M−H); HPLC-Method A, R_(t) 3.09 min.

Example 10(5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-10)

Prepared by Method C in ethanol in 35% yield. ¹HNMR (500 MHz, DMSO-d6) δ13.2 (s, 1H), 10.1 (s, br, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.66 (m,4H), 7.57 (d, 1H), 2.79 (m, 2H), 2.73 (m, 2H), 1.89 (m, 4H) ppm. MS(ES+) 478.45 (M+H), (ES−) 476.42 (M−H); HPLC-Method A, R_(t) 3.21 min.

Example 11(5,7-difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-11)

Prepared in 60% yield. White solid. ¹HNMR (500 MHz, DMSO-d6) δ 1.72 (m,4H), 1.91 (m, 2H), 3.01 (m, 4H), 7.15 (dd, 1H), 7.30 (td, 1H), 7.66 (m,2H), 7.72 (t, 1H), 7.78 (d, 1H), 10.2 (m, 1H), 13.5 (br. s, 1H); EI-MS460.2 (M+H); HPLC-Method A, R_(t) 3.13 min.

Example 12(6-Benzyl-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-fluoro-1H-indazol-3-yl)-amine(II-12)

Prepared in 49% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.8 (s, 1H), 9.11 (s,1H), 7.68 (d, 1H), 7.58 (t, 1H), 7.53 (t, 1H), 7.44 (m, 4H), 7.37 (t,2H), 7.29 (t, 1H), 7.19 (m, 2H), 3.78 (s, 2H), 3.61 (s, 2H), 2.81 (s,br, 4H) ppm; LC-MS (ES+) 519.24 (M+H); HPLC-Method A, R_(t) 3.11 min.

Example 13(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-13)

Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.70 (m, 4H), 1.90 (m,2H), 3.00 (m, 4H), 7.01 (t, 1H), 7.30 (td, 1H), 7.44 (d, 1H), 7.49 (d,1H), 7.68 (m, 3H), 7.77 (d, 1H), 10.01 (m, 1H), 12.83 (s, 1H); EI-MS424.2 (M+H); HPLC-Method A, R_(t) 3.17 min.

Example 14(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-14)

Prepared in 78% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.71 (m, 4H), 1.91 (m,2H), 3.00 (m, 4H), 6.98 (td, 1H), 7.16 (dd, 1H), 7.31 (d, 1H), 7.68 (m,3H), 7.77 (d, 1H), 10.25 (m, 1H), 13.40 (br. s, 1H); EI-MS 442.2 (M+H);HPLC-Method A, R_(t) 3.12 min.

Example 15(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-amine(II-15)

Prepared in 63% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.71 (m, 4H), 1.91 (m,2H), 3.00 (m, 4H), 7.20 (td, 1H), 7.25 (dd, 1H), 7.49 (dd, 1H), 7.69(br. t, 2H), 7.74 (m, 1H), 7.79 (d, 1H), 10.35 (m, 1H), 13.00 (br. s,1H); EI-MS 442.2 (M+H); HPLC-Method A, R_(t) 3.21 min.

Example 16(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine(II-16)

A solution of compound II-12 (45 mg, 0.087 mmol) in methanol (4.4%HCOOH) was treated with an equal weight of Pd/C (10%) at roomtemperature for 14 h. The mixture was filtered through celite, thefiltrate evaporated, and the crude product was purified by preparativeHPLC to provide 15 mg (41%) of the desired product as yellow solid.¹HNMR (500 MHz, DMSO-d6) δ 12.9 (s, 1H), 9.52 (s, 1H), 9.32 (s, 2H,TFA-OH), 7.72 (d, 1H), 7.59 (m, 2H), 7.49 (m, 2H), 7.21 (m, 1H), 7.15(m, 1H), 4.31 (s, 2H), 3.55 (s, 2H), 3.00 (m, 2H) ppm; LC-MS (ES+)429.20 (M+H); HPLC-Method A, R_(t) 2.79 min.

Example 17(1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(II-17)

Prepared in 58% yield. ¹HNMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H), 10.3 (s,br, 1H), 7.74 (m, 4H), 7.51 (d, 1H), 7.47 (d, 1H), 7.32 (t, 1H), 7.03(t, 1H), 2.82 (m, 2H), 2.73 (m, 2H), 1.90 (m, 4H) ppm; LC-MS (ES+)410.21 (M+H); HPLC-Method A, R_(t) 2.99 min.

Example 18(7-Benzyl-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-fluoro-1H-indazol-3-yl)-amine(II-18)

Prepared from compound B11 in 92% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.9(s, 1H), 10.5 (s, br, 1H), 9.58 (s, 1H, TFA-OH), 7.71 (d, 1H), 7.52 (m,9H), 7.19 (m, 2H), 4.57 (s, 2H), 4.20 (m, 2H), 3.70 (m, 2H), 3.00 (m,2H) ppm; LC-MS (ES+) 519.23 (M+H); HPLC-Method A, R_(t) 3.23 min.

Example 19(1H-Indazol-3-yl)-[6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-19)

Prepared in 42% yield. Melting point 235-237° C.; ¹HNMR (500 MHz, DMSO)δ 2.44 (3H, s), 7.09 (1H, J=7.5 Hz, t), 7.40 (1H, J=7.1 Hz, t), 7.49(1H, J=8.3 Hz, d), 7.70 (3H, m), 7.79 (1H, J=7.3 Hz, t), 7.87 (1H, J=8.3Hz, d), 8.03 (1H, J=7.7 Hz, d), 10.3 (1H, s), 12.6 (1H, s) ppm;HPLC-Method A, R_(t) 2.958 min; MS (FIA) 370.2 (M+H)⁺.

Example 20(1H-Indazol-3-yl)-[6-phenyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-20)

Prepared in 32% yield. ¹HNMR (500 MHz, DMSO) δ 6.94 (1H, J=7.4 Hz, t),7.24 (1H, J=7.4 Hz, t), 7.33 (1H, J=8.4 Hz, d), 7.42 (3H, m), 7.57 (1H,J=7.3 Hz, t), 7.68 (2H, m), 7.75 (1H, J=7.9 Hz, d), 7.93 (3H, m), 8.18(1H, br s), 10.45 (1H, br s), 12.5 (1H, br s) ppm; HPLC-Method A, R_(t)4.0 min; MS (FIA) 432.2 (M+H)⁺.

Example 21(1H-Indazol-3-yl)-[6-(pyridin-4-yl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-21)

Prepared in 12% yield. ¹HNMR (500 MHz, DMSO) δ 7.16 (1H, J=7.4 Hz, t),7.46 (1H, J=7.6 Hz, t), 7.56 (1H, J=8.3 Hz, d), 7.80 (1H, J=7.2 Hz, t),7.90 (2H, m), 7.97 (1H, J=7.8 Hz, d), 8.09 (1H, br), 8.22 (2H, J=4.9 Hz,d), 8.45 (1H, br s), 8.93 (2H, J=4.8 Hz, d), 10.9 (1H, br s), 12.8 (1H,br s) ppm; HPLC-Method A, R_(t) 3.307 min; MS (FIA) 433.2 (M+H)⁺

Example 22(1H-Indazol-3-yl)-[6-(pyridin-2-yl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-22)

Prepared in 42% yield. ¹HNMR (500 MHz, DMSO) δ 7.07 (1H, J=7.4 Hz, t),7.36 (1H, J=7.4 Hz, t), 7.46 (1H, J=7.4 Hz, d), 7.53 (1H, J=5.0 Hz, t),7.70 (1H, J=7.4 Hz, t), 7.79 (1H, J=7.1 Hz, t), 7.83 (1H, J=7.4 Hz, d),7.88 (1H, J=7.8 Hz, d), 7.97 (1H, J=7.7 Hz, t), 8.02 (1H, J=5.5 Hz, brd), 8.36 (1H, J=7.8 Hz, d), 8.75 (2H, J=4.1 Hz, d), 10.5 (1H, br s),12.7 (1H, br s) ppm; HPLC-Method A, R_(t) 3.677 min; MS (FIA) 433.2(M+H)⁺.

Example 23[6-(2-Chlorophenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-23)

Prepared in 44% yield; ¹HNMR (500 MHz, DMSO) δ 7.08 (1H, J=7.5 Hz, t),7.37 (1H, J=7.5 Hz, t), 7.45 (1H, J=8.4 Hz, d), 7.51 (2H, m), 7.61 (1H,J=7.4, 1.9 Hz, dd), 7.69 (2H, m), 7.79 (2H, J=4.0 Hz, d), 7.86 (3H,J=7.8 Hz, d), 8.04 (2H, J=6.2 Hz, br d), 10.7 (1H, br s), 12.6 (1H, brs) ppm; HPLC-Method A, R_(t) 3.552 min; MS (FIA) 466.2 (M+H)⁺.

Example 24[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-24)

Prepared in 35% yield; mp 183-186° C.; ¹HNMR (500 MHz, DMSO) δ 2.14 (3H,s), 2.27 (3H, s), 6.85 (1H, J=7.5 Hz, t), 7.15 (1H, J=7.6 Hz, t), 7.32(3H, m), 7.38 (1H, J=7.5 Hz, t), 7.42 (1H, J=7.4 Hz, t), 7.53 (1H, J=7.6Hz, d), 8.88 (1H, s), 12.5 (1H, s) ppm; HPLC-Method A, R_(t) 2.889 min.;MS (FIA) 384.2 (M+H)′.

Example 25[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-25)

Prepared in 44% yield. Melting point 160-163° C.; ¹HNMR (500 MHz, DMSO)δ 2.27 (3H, s), 2.40 (3H, s), 7.16 (2H, m), 7.44 (2H, m), 7.52 (1H,J=7.4 Hz, t), 7.57 (1H, J=7.4 Hz, t), 7.67 (1H, J=7.8 Hz, d), 9.03 (1H,s), 12.75 (1H, s) ppm; HPLC-Method A, R_(t) 2.790 min; MS (FIA) 402.2(M+H)⁺.

Example 26[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-26)

Prepared in 30% yield. ¹HNMR (500 MHz, DMSO) δ 2.14 (3H, s), 2.33 (3H,s), 6.84 (1H, J=7.4 Hz, t), 7.13 (1H, J=7.4 Hz, t), 7.19 (1H, J=6.9 Hz,br t), 7.27 (1H, J=7.4 Hz, d), 7.32 (3H, br m), 7.37 (1H, J=7.1 Hz, d),10.0 (1H, br), 12.8 (1H, br s) ppm; 8 2.919 min; MS (FIA) 350.1 (M+H)⁺.

Example 27[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-27)

Prepared in 92% yield. ¹HNMR (500 MHz, DMSO) δ 2.33 (3H, s), 2.50 (3H,s), 6.97 (1H, m), 7.15 (1H, m), 7.30 (1H, J=8.1 Hz, d), 7.65 (3H, m),7.76 (1H, J=7.5 Hz, d), 10.0 (1H, s), 13.4 (1H, s) ppm; HPLC-Method A,R_(t) 3.053 min; MS (FIA) 402.2 (M+H)⁺.

Example 28(5,7-Difluoro-1H-indazol-3-yl)-[5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-28)

Prepared in 50% yield. ¹HNMR (500 MHz, DMSO) δ 2.42 (3H, s), 2.63 (3H,s), 7.22 (1H, J=7.6 Hz, d), 7.38 (1H, J=9.3, 1.7 Hz, dt), 7.71 (1H, m),7.75 (1H, J=7.0 Hz, d), 7.79 (1H, J=6.7 Hz, d), 7.86 (1H, J=8.0 Hz, d),10.0 (1H, s), 13.2 (1H, s) ppm; HPLC-Method A, R_(t) 3.111 min; MS (FIA)420.2 (M+H)⁺.

Example 29[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-29)

Prepared in 58% yield. ¹HNMR (500 MHz, DMSO) δ 2.47 (3H, s), 2.66 (3H,s), 7.44 (2H, m), 7.53 (1H, m), 7.64 (3H, m), 10.4 (1H, br), 13.8 (1H,br s) ppm; HPLC-Method A, R_(t) 2.921 min; MS (FIA) 386.1 (M+H)⁺.

Example 30[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-30)

Prepared in 70% yield. ¹HNMR (500 MHz, DMSO) δ 2.35 (3H, s), 2.51 (3H,s), 7.03 (1H, J=7.8, 4.4 Hz, dt), 7.22 (1H, m), 7.33 (1H, J=7.4 Hz, t),7.42 (1H, m), 9.19 (1H, s), 13.3 (1H, s) ppm; HPLC-Method A, R_(t) 2.859min; MS (FIA) 368.2 (M+H)⁺.

Example 31[2-(2-Chlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-31)

Prepared in 86% yield. 1HNMR (500 MHz, DMSO) δ 2.49 (3H, s), 2.68 (3H,s), 7.38 (1H, J=9.0 Hz, t), 7.54 (2H, m), 7.67 (4H, m), 10.5 (1H, br),13.2 (1H, br s) ppm; HPLC-Method A, R_(t) 2.850 min; MS (FIA) 368.1(M+H)⁺.

Example 32[2-(2,4-Dichlorophenyl)-5,6-dimethyl-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-32)

Prepared in 52% yield. ¹HNMR (500 MHz, DMSO) δ 2.46 (3H, s), 2.64 (3H,s), 7.16 (1H, J=7.5 Hz, t), 7.46 (1H, J=7.6 Hz, t), 7.61 (2H, m), 7.68(2H, J=8.2 Hz, d), 7.82 (1H, m), 10.2 (1H, br), 13.0 (1H, br s) ppm;HPLC-Method A, R_(t) 2.983 min; MS (FIA) 384.1 (M+H).

Example 33(5-Methyl-2H-pyrazol-3-yl)-[2-(2-methylphenyl)-quinazolin-4-yl]-amine(II-33)

¹HNMR (DMSO) δ 1.21 (3H,s), 2.25 (3H, s), 6.53 (1H, s), 7.38 (4H, m),7.62 (1H, d), 7.73 (1H, d), 7.81 (1H, d), 7.89 (1H, t), 8.70 (1H, s),12.20 (1H, s); MS 316.3 (M+H)⁺.

Example 34[2-(2,4-Difluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-34)

¹HNMR (500 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.58 (d,1H), 7.97 (m, 1H), 8.36 (m, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 6.62 (s,1H), 2.30 (s, 3H); MS 338.07 (M+H).

Example 35[2-(2,5-Dimethoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-35)

¹HNMR (500 MHz, DMSO-d6) δ 12.5 (br s, 1H), 8.68 (br, 1H), 7.92 (t,J=7.5 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.45 (s,1H), 7.14 (m, 2H), 6.51 (s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 2.14 (s,3H); MS 362.2 (M+H).

Example 36[2-(2-Chlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-36)

¹HNMR (500 MHz, DMSO-d6) δ 11.8 (br, 1H), 8.80 (d, J=8.3 Hz, 1H), 8.00(t, J=7.6 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.78 (m, 2H), 7.67 (d, J=7.8Hz, 1H), 7.61 (t, J=7.0 Hz, 1H), 7.55 (t, J=7.4 Hz, 1H), 6.56 (s, 1H),2.18 (s, 3H); MS 336.1 (M+H).

Example 37[2-(2-Methoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-37)

¹HNMR (500 MHz, DMSO-d6) δ 8.78 (s, br, 1H), 8.00 (t, J=7.4 Hz, 1H),7.90 (m, 2H), 7.74 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.3 Hz, 1H), 7.30 (d,J=8.4 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.58 (s, br, 1H), 3.90 (s. 3H),2.21 (s, 3H); MS 332.1 (M+H).

Example 38[2-(2,6-Dimethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-38)

¹HNMR (500 MHz, DMSO-d6) δ 12.2 (s, br, 2H), 8.88 (d, J=7.7 Hz, 1H),8.05 (t, J=7.7 Hz, 1H), 7.80 (m, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.21 (d,J=7.7 Hz, 2H), 6.36 (s, 1H), 2.16 (s, 3H), 2.15 (s, 6H); MS 330.1 (M+H).

Example 39[2-(2-Acetylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-39)

¹HNMR (500 MHz, DMSO-d6) δ 12.35 (s, br, 1H), 8.93 (d, J=8.4 Hz, 1H),8.37 (d, J 8.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 8.11 (t, J=8.0 Hz, 2H),7.89 (m, 2H), 7.77 (m, 2H), 6.93 (s, 1H), 2.33 (s, 3H), 2.04 (s, 3H) MS344.1 (M+H).

Example 40[2-(2,3-Dimethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-40)

¹HNMR (500 MHz, DMSO-d6) δ 12.6 (s, br, 1H), 12.1 (s, br, 1H), 8.91 (d,J=7.7 Hz, 1H), 8.14 (t, J=7.2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.89 (t,J=7.7 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.53 (d, J=7.0 Hz, 1H), 7.42 (t,J=7.6 Hz, 1H), 6.60 (s, 1H), 2.43 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H);MS 330.1 (M+H).

Example 41(5-Methyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-41)

¹HNMR (500 MHz, DMSO-d6) δ 12.3 (s, 1H), 10.5 (s, 1H), 8.77 (d, J=8.2Hz, 1H), 7.92 (m, 2H), 7.85 (m, 3H), 7.56 (t, J=8.1 Hz, 1H), 7.67 (t,J=7.4 Hz, 1H), 6.63 (s, 1H), 2.27 (s, 3H); MS 370.1 (M+H).

Example 42[2-(2-Ethylphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-42)

¹HNMR (500 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.02 (s, br, 1H), 7.82 (d, J8.4 Hz, 1H), 7.77 (m, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.54 (m, 1H), 7.41(m, 2H), 6.40 (s, 1H), 2.75 (q, J 7.1 Hz, 2H), 2.17 (s, 3H), 0.99 (t,J=7.5 Hz, 3H); MS 330.1 (M+H).

Example 43(2-Biphenyl-2-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(II-43)

¹HNMR (500 MHz, DMSO-d6) δ 8.76 (d, J=7.6 Hz, 1H), 8.04 (m, 1H), 7.75(m, 6H), 7.30 (m, 5H), 5.34 (s, 1H), 2.14 (s, 3H); MS 378.2 (M+H).

Example 44[2-(2-Hydroxyphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-44)

¹HNMR (500 MHz, DMSO-d6) δ 10.9 (s, br, 1H), 8.62 (d, J=8.2 Hz, 1H),8.28 (d, J 7.9 Hz, 1H), 7.87 (m, 2H), 7.60 (t, J=7.9 Hz, 1H), 7.37 (t,J=7.8 Hz, 1H), 6.92 (m, 2H), 6.45 (s, 1H), 2.27 (s, 3H); MS 318.1 (M+H).

Example 45[2-(2-Ethoxyphenyl)-quinazolin-4-yl]-(5-Methyl-2H-pyrazol-3-yl)-amine(II-45)

¹HNMR (500 MHz, DMSO-d6) δ 12.1 (s, br, 1H), 8.75 (d, J=8.3 Hz, 1H),7.97 (t, J=7.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H),7.70 (t, J=7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H),7.12 (t, J=7.6 Hz, 1H), 6.55 (s, 1H), 4.11 (q, J=6.9 Hz, 2H), 2.16 (s,3H), 1.22 (t, J=6.9 Hz, 3H); MS 346.1 (M+H).

Example 46[5-(Thiophen-2-yl)-2H-pyrazol-3-yl]-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-46)

¹HNMR (500 MHz, DMSO-d6) δ 8.04 (d, J=8.3 Hz, 1H), 8.05 (dd, J=7.3, 8.2Hz, 1H), 7.93 (d, J=6.5 Hz, 1H), 7.81 (m, 5H), 7.34 (d, J=5.0 Hz, 1H),7.25 (m, 1H), 7.00 (m, 1H), 6.87 (s, 1H); MS 438.1 (M+H).

Example 47[4-(Thiophen-2-yl)-2H-pyrazol-3-yl]-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-47)

Prepared according to Method B. ¹HNMR (500 MHz, DMSO-d6) δ 6.97 (m, 1H),7.08 (m, 1H), 7.27 (m, 1H), 7.36 (m, 1H), 7.66 (m, 2H), 7.77 (m, 3H),7.83 (m, 1H), 8.00 (m, 1H), 8.18 (s, 1H), 8.62 (d, J=8.2 Hz, 1H), 10.7(br. s, 1H); EI-MS 438.1 (M+H); HPLC-Method A, R_(t) 2.97 min.

Example 48(4-Phenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-48)

Prepared according to Method B. ¹HNMR (500 MHz, DMSO-d6) δ 7.05 (br. s,1H), 7.14 (t, J=7.8 Hz, 1H), 7.25 (m, 3H), 7.43 (m, 2H), 7.60 (m, 2H),7.73 (m, 2H), 7.80 (d, 1H), 7.95 (m, 1H), 8.12 (br. s, 1H), 8.60 (m,1H), 10.6 (br. s, 1H); EI-MS 432.2 (M+H); HPLC-Method A, R_(t) 3.04 min.

Example 49(5-tert-Butyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-49)

¹HNMR (500 MHz, DMSO-d6) δ 8.76 (d, J=8.3 Hz, 1H), 7.94 (m, 2H), 7.79(m, 4H), 7.70 (t, J=7.6 Hz, 1H), 6.51 (s, 1H), 1.16 (s, 9H); MS 412.2(M+H).

Example 50(5-Phenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-50)

¹HNMR (500 MHz, DMSO-d6) δ 7.09 (s, 1H), 7.36 (td, J=7.8, 1.1 Hz, 1H),7.46 (t, J=7.8 Hz, 2H), 7.65 (br. d, J=8.1 Hz, 2H), 7.78 (m, 2H), 7.90(m, 4H), 7.95 (d, J=7.7 Hz, 1H), 8.00 (t, J=7.8 Hz, 1H), 8.81 (d, J=8.6Hz, 1H), 11.29 (br. s, 1H); EI-MS 432.1 (M+H); HPLC-Method A, R_(t) 3.24min.

Example 51(4,5-Diphenyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-51)

¹HNMR (500 MHz, DMSO-d6) δ 7.13 (m, 1H), 7.18 (m, 5H), 7.36 (m, 5H),7.62 (m, 3H), 7.73 (m, 2H), 7.85 (m, 1H), 8.48 (d, J=8.7 Hz, 1H), 10.02(s, 1H), 13.19 (s, 1H); EI-MS 508.2 (M+H); HPLC-Method A, R_(t) 3.39min.

Example 52(4-Carbamoyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-52)

Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6): δ 12.85 (s, 1H), 12.77(s, 1H), 11.80 (s, 1H), 10.80 (s, 1H), 8.35-7.42 (m, 9H); MS 399.13(M+H) HPLC-Method A, R_(t) 2.782 min.

Example 53(2H-Pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-53)

Prepared in 38% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.65(s, 1H), 8.75 (d, 1H), 7.91-7.68 (m, 8H), 6.87 (s, 1H). MS: (M+H)356.17. HPLC-Method A, R_(t) 2.798 min.

Example 54(5-Hydroxy-2H-pyrazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(II-54)

Prepared in 36% yield; ¹HNMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.75(s, 1H), 8.03-7.75 (m, 9H), 5.97 (s, 1H); MS 372.18 (M+H); HPLC-MethodA, R_(t) 2.766 min.

Example 55(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-55)

Prepared in 30% yield. ¹HNMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.45(s, 1H), 8.68 (s, 1H), 7.89-7.45 (m, 8H), 6.48 (s, 1H), 0.89 (m, 2H),0.62 (s, 2H). MS 396.18 (M+H); HPLC-Method A, R_(t) 3.069 min.

Example 56(5-Methoxymethyl-2H-pyrazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-56)

Prepared in 33% yield; ¹HNMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.48(s, 1H), 8.60 (s, 1H), 7.81-7.55 (m, 7H), 6.71 (s, 1H), 4.28 (s, 2H),3.18 (s, 3H). MS 400.19 (M+H): HPLC-Method A, R_(t) 2.881 min.

Example 57(1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-57)

Prepared to afford 51 mg (78% yield) as pale yellow solid. ¹HNMR (500MHz, DMSO-d6) δ 12.7 (s, 1H), 10.4 (s, 1H), 8.55 (d, 1H), 7.81 (t, 1H),7.71 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.46 (m, 4H), 7.36 (d, 1H),7.22 (t, 1H), 6.91 (t, 1H) ppm; LC-MS (ES+) 406.16 (M+H), (ES−) 404.19(M−H); HPLC-Method A, R_(t) 3.00 min.

Example 58(4-Chloro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-58)

Prepared in DMF (70% yield) as pale yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.3 (s, br, 1H), 10.9 (s, br, 1H), 8.60 (d, 1H), 7.97 (t,1H), 7.81 (d, 1H), 7.75 (t, 1H), 7.67 (d, 1H), 7.63 (dd, 1H), 7.57 (m,2H), 7.43 (d, 1H), 7.28 (dd, 1H), 7.08 (d, 1H) ppm; LC-MS (ES+) 440.10(M+H), (ES−) 438.12 (M−H); HPLC-Method A, R_(t) 3.08 min.

Example 59(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-59)

Prepared in DMF (34% yield) as pale yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.0 (s, 1H), 10.6 (s, 1H), 8.72 (d, 1H), 7.99 (t, 1H), 7.89(d, 1H), 7.79 (d, 1H), 7.75 (t, 1H), 7.68 (m, 3H), 7.56 (dd, 1H), 7.39(d, 1H), 7.28 (t, 1H) ppm; LC-MS (ES+) 424.12 (M+H), (ES−) m/e=422.13(M−H); HPLC-Method A, R_(t) 3.05 min.

Example 60(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-60)

Prepared in DMF (51% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.4 (s, 1H), 10.6 (s, 1H), 8.68 (d, 1H), 7.95 (t, 1H), 7.85 (d, 1H),7.72 (m, 2H), 7.63 (m, 2H), 7.58 (m, 1H), 7.43 (d, 1H), 7.18 (dd, 1H),7.00 (m, 1H) ppm; LC-MS (ES+) 424.11 (M+H), (ES−) 422.15 (M−H);HPLC-Method A, R_(t) 3.06 min.

Example 61(5-Methyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-61)

Prepared in DMF (81% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.0 (s, br, 1H), 8.79 (br, 1H), 8.11 (br, 1H), 7.96 (d, 1H), 7.82 (m,5H), 7.46 (s, 1H), 7.41 (d, 1H), 7.20 (d, 1H), 2.33 (s, 3H) ppm; MS(ES+) 420.15 (M+H), (ES−) 418.17 (M−H); HPLC-Method A, R_(t) 3.07 min.

Example 62[2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-62)

Prepared in DMF (37% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.0 (s, 1H), 10.8 (s, 1H), 8.72 (d, 1H), 7.97 (t, 1H), 7.90 (d, 1H),7.75 (t, 1H), 7.53 (m, 3H), 7.43 (t, 1H), 7.35 (d, 1H), 7.23 (t, 1H)ppm; LCMS (ES+) 424.08 (M+H), (ES−) 422.10 (M−H); HPLC-Method A, R_(t)3.06 min.

Example 63 [2-(2-Chloro-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-63)

Prepared in 91% yield. ¹HNMR (500 MHz, DMSO-d6) δ 7.06 (t, 1H), 7.36 (t,1H), 7.39 (t, 1H), 7.52 (m, 3H), 7.62 (d, 1H), 7.72 (d, 1H), 7.82 (m,1H), 7.90 (d, 1H), 8.05 (m, 1H), 8.76 (d, 1H), 11.5 (m, 1H), 13.02 (s,1H); EI-MS 372.1 (M+1); HPLC-Method A, R_(t) 2.93 min.

Example 64(5-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-64)

Prepared in DMF (57% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.4 (s, br, 1H), 11.4 (br, 1H), 8.72 (d, 1H), 8.12 (s, 1H), 7.98 (t,1H), 7.83 (d, 1H), 7.76 (d, 1H), 7.73 (dd, 1H), 7.60 (m, 4H), 7.52 (d,1H) ppm; LC-MS (ES+) 474.12 (M+H), (ES−) 472.17 (M−H); HPLC-Method A,R_(t) 3.25 min.

Example 65(4-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-65)

Prepared in DMF (8% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.7 (s, br, 1H), 11.2 (br, 1H), 8.70 (d, 1H), 8.05 (s, 1H), 7.85 (m,3H), 7.65 (m, 4H), 7.51 (m, 2H) ppm; LC-MS (ES+) 474.13 (M+H), (ES−)472.17 (M−H); HPLC-Method A, R_(t) 3.15 min.

Example 66[2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-66)

Prepared in DMF (30% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ12.9 (s, 1H), 11.1 (s, 1H), 8.69 (d, 1H), 7.95 (t, 1H), 7.82 (d, 1H),7.73 (t, 1H), 7.56 (d, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.39 (m, 2H),7.26 (t, 1H), 6.92 (t, 1H) ppm; LC-MS (ES+) 406.11 (M+H), (ES−) 404.12(M−H); HPLC-Method A, R_(t) 3.00 min.

Example 67 (1H-indazol-3-yl)-[2-(2-methyl-phenyl)-quinazolin-4-yl]-amine(II-67)

Prepared in 55% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.15 (s, 3H), 7.09 (t,1H), 7.26 (d, 1H), 7.31 (t, 1H), 7.39 (t, 1H), 7.42 (m, 1H), 7.55 (d1H), 7.64 (d, 1H), 7.74 (d, 1H), 7.89 (m, 1H), 7.96 (d, 1H), 8.10 (m,1H), 8.81 (d, 1H), 12.0 (m, 1H), 13.18 (s, 1H); EI-MS 352.2 (M+1);HPLC-Method A, R_(t) 2.93 min.

Example 68(7-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-68)

Prepared in DMF (75% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.5 (s, br, 1H), 11.2 (s, br, 1H), 8.68 (d, 1H), 7.97 (t, 1H), 7.92 (d,1H), 7.82 (d, 1H), 7.74 (t, 1H), 7.70 (d, 1H), 7.68 (d, 1H), 7.64 (m,2H), 7.57 (m, 1H), 7.14 (t, 1H) ppm; LC-MS (ES+) 474.11 (M+H), (ES−)472.14 (M−H); HPLC-Method A, R_(t) 3.24 min.

Example 69(6-Trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-69)

Prepared by Method B in DMF (78% yield) as yellow solid. ¹HNMR (500 MHz,DMSO-d6) δ 13.4 (s, br, 1H), 11.1 (s, br, 1H), 8.67 (d, 1H), 7.95 (t,1H), 7.82 (m, 3H), 7.72 (m, 2H), 7.63 (m, 2H), 7.57 (t, 1H), 7.23 (d,1H) ppm; LC-MS (ES+) 474.12 (M+H), (ES−) 472.15 (M−H); HPLC-Method A,R_(t) 3.28 min.

Example 70(5-Nitro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-70)

Prepared in DMF (82% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.6 (s, br, 1H), 11.4 (s, br, 1H), 8.75 (s, 1H), 8.72 (d, 1H), 8.09(dd, 1H), 7.98 (t, 1H), 7.83 (d, 1H), 7.75 (t, 1H), 7.70 (m, 2H), 7.61(m, 3H) ppm; LC-MS (ES+) 451.14 (M+H), (ES−) 449.12 (M−H); HPLC-MethodA, R_(t) 3.02 min.

Example 71(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-71)

Prepared in DMF (60% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.7 (s, br, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t, 1H), 7.88 (d,1H), 7.80 (m, 2H), 7.70 (m, 3H), 7.32 (m, 2H) ppm; LC-MS (ES+) 442.14(M+H), (ES−) 440.14 (M−H); HPLC-Method A, R_(t) 3.11 min.

Example 72(4-Pyrrol-1-yl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-72)

Prepared in DMF (33% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.4 (s, br, 1H), 11.0 (s, br, 1H), 8.53 (d, 1H), 7.98 (t, 1H), 7.75 (m,4H), 7.62 (m, 2H), 7.52 (d, 1H), 7.43 (t, 1H), 7.05 (d, 1H), 6.80 (s,2H), 5.61 (s, 2H) ppm; LC-MS (ES+) 471.18 (M+H), (ES−) 469.18 (M−H);HPLC-Method A, R_(t) 3.12 min.

Example 73(5-Amino-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-73)

A solution of compound II-70 (70 mg, 0.16 mmol) in MeOH (2 mL) wastreated with Raney Ni until solution was colorless (about 1.5 g Raney Niwas added). After stirring at room temperature for 40 min, the mixturewas filtered through celite, the resulting celite was washed with MeOH(5 times), and the solvent was evaporated in vacuo to provide a crudeproduct that was then purified by HPLC to give the title compound as ayellow solid (10 mg, 15%). m.p. 221-223° C.; ¹HNMR (500 MHz, DMSO-d6) δ13.2 (s, br, 1H), 10.7 (s, br, 1H), 9.80 (br, 2H), 8.68 (d, 1H), 7.97(t, 1H), 7.87 (d, 1H), 7.75 (m, 2H), 7.65 (m, 5H), 7.30 (d, 1H) ppm; MS(ES+) 421.16 (M+H), (ES−) 419.17 (M−H); HPLC-Method A, R_(t) 2.41 min.

Example 74[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-74)

Prepared in DMF (35% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.7 (s, 1H), 11.7 (s, br, 1H), 8.80 (d, 1H), 8.15 (t, 1H), 7.99 (d,1H), 7.88 (t, 1H), 7.68 (d, 1H), 7.60 (m, 2H), 7.53 (t, 1H), 7.46 (t,1H), 7.25 (dd, 1H), 7.04 (m, 1H) ppm; LC-MS (ES+) 390.16 (M+H);HPLC-Method A, R_(t) 3.00 min.

Example 75[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-75)

Prepared in DMF. ¹HNMR (500 MHz, DMSO-d6) δ 13.2 (s, 1H), 11.7 (s, br,1H), 8.80 (d, 1H), 8.10 (t, 1H), 7.91 (m, 2H), 7.70 (d, 1H), 7.58 (m,4H), 7.50 (t, 1H), 7.29 (t, 1H) ppm; LC-MS (ES+) 390.17 (M+H);HPLC-Method A, R_(t) 3.00 min.

Example 76[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-76)

Prepared in DMF (55% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.8 (s, 1H), 11.5 (s, br, 1H), 8.76 (d, 1H), 8.08 (t, 1H), 7.93 (d,1H), 7.84 (t, 1H), 7.64 (d, 1H), 7.55 (d, 1H), 7.50 (t, 1H), 7.44 (m,2H), 7.36 (t, 1H) ppm; LC-MS (ES+) 408.15 (M+H), (ES−) 406.17 (M−H);HPLC-Method A, R_(t) 3.08 min.

Example 77[2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5-trifluoromethyl-1H-indazol-3-yl)-amine(II-77)

Prepared in DMF (66% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.5 (s, 1H), 11.4 (s, br, 1H), 8.79 (d, 1H), 8.29 (s, 1H), 8.07 (t,1H), 7.93 (d, 1H), 7.84 (t, 1H), 7.72 (d, 1H), 7.63 (d, 2H), 7.53 (d,1H), 7.48 (t, 1H), 7.36 (t, 1H) ppm; LC-MS (ES+): m/e=440.16 (M+H);(ES−): m/e=438.18 (M−H); HPLC-Method A, R_(t) 3.22 min.

Example 78 [2-(2-cyano-phenyl)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(II-78)

Prepared in 13% yield. ¹H-NMR (500 MHz, DMSO) δ 12.9 (br, 1H), 10.8 (br,1H), 8.73 (br s, 1H), 7.97 (m, 4H), 7.74 (m, 1H), 7.5 (m, 4H), 7.42 (m,1H), 7.08 (m, 1H) ppm; MS (FIA) 363.2 (M+H); HPLC-Method A, R_(t) 2.971min.

Example 79(5-Bromo-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-79)

Prepared in DMF (64% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.4 (s, 1H), 11.6 (s, br, 1H), 8.93 (d, 1H), 8.21 (t, 1H), 8.14 (s,1H), 8.05 (d, 1H), 7.95 (m, 4H), 7.86 (t, 1H), 7.65 (d, 1H), 7.59 (d,1H) ppm; MS (ES+) 486.10 (M+H), (ES−) 484.09 (M−H); HPLC-Method A, R_(t)3.22 min.

Example 80(6-Chloro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-80)

Prepared in DMF (94% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.1 (s, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t, 1H), 7.87 (d,1H), 7.79 (m, 2H), 7.73 (m, 2H), 7.67 (m, 2H), 7.58 (s, 1H), 7.04 (dd,1H) ppm. LC-MS (ES+) 440.14 (M+H), (ES−) 438.16 (M−H); HPLC-Method A,R_(t) 3.25 min.

Example 81(7-Fluoro-6-trifluoromethyl-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-81)

Prepared in DMF (30% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.9 (s, 1H), 11.0 (s, br, 1H), 8.64 (d, 1H), 7.94 (t, 1H), 7.81 (d,1H), 7.71 (m, 2H), 7.60 (m, 4H), 7.20 (dd, 1H) ppm. LC-MS (ES+) 492.18(M+H), (ES−) 490.18 (M−H); HPLC-Method A, R_(t) 3.44 min.

Example 82(6-Bromo-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-82)

Prepared in DMF (40% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.1 (s, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.03 (t, 1H), 7.87 (d,1H), 7.80 (m, 2H), 7.73 (m, 3H), 7.67 (m, 1H), 7.61 (d, 1H), 7.15 (dd,1H) ppm; MS (ES+) 486.07 (M+H); HPLC-Method A, R_(t) 3.28 min.

Example 83[2-(2,4-Bis-trifluoromethyl-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-83)

Prepared in DMF in 28% yield. ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d, J=8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC-MS (ES+) 510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

Example 84(5,7-Difluoro-1H-indazol-3-yl)-[2-(4-fluoro-2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-84)

Prepared in 48% yield. ¹HNMR (500 MHz, MeOH-d4) δ 8.74-8.63 (m, 1H),8.23-8.10 (m, 1H), 7.99-7.90 (m, 2H), 7.89-7.80 (m, 1H), 7.71-7.61 (m,1H), 7.61-7.50 (m, 1H), 7.24-7.15 (m, 1H), 7.14-7.02 (m, 1H); LC-MS(ES+) 460.14 (M+H); HPLC-Method C, R_(t) 7.59 min.

Example 85[2-(2-Bromo-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-85)

Prepared in THF (21% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d, J=8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC-MS (ES+) 510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

Example 86(5,7-Difluoro-1H-indazol-3-yl)-[2-(5-fluoro-2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-86)

Prepared in THF (26% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.62 (d, J=8.4Hz, 1H), 8.16-8.02 (m, 1H), 7.96-7.73 (m, 3H), 7.59-7.48 (m, 1H),7.48-7.35 (m, 1H), 7.21-7.09 (m, 1H), 7.09-6.89 (m, 1H); LC-MS (ES+)460.16 (M+H); HPLC-Method C, R_(t) 7.28 min.

Example 87[2-(2,4-Dichloro-phenyl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-87)

Prepared in THF (16% yield). ¹HNMR (500 MHz, MeOH-d4) δ 8.81 (d, J=8.4Hz, 1H), 8.35-8.20 (m, 3H), 8.19-7.96 (m, 3H), 7.40-7.34 (m, 1H),7.29-7.14 (m, 1H); LC-MS (ES+) 510.14 (M+H); HPLC-Method C, R_(t) 8.29min.

Example 88[2-(2-Chloro-5-trifluoromethyl-phenyl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-88)

Prepared in THF (33% yield). 1HNMR (500 MHz, DMSO-d6) δ 10.76 (s, 1H),8.66 (d, J=8.3 Hz, 1H), 8.06-7.84 (m, 3H), 7.81-7.63 (m, 3H), 7.48-7.16(m, 2H); LC-MS (ES+) 476.16 (M+H); HPLC-Method C, R_(t) 19.28 min.

Example 89(4-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-89)

Prepared in NMP (79% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.2 (s, 1H), 10.8 (s, br, 1H), 8.63 (d, 1H), 7.97 (t, 1H), 7.85 (d,1H), 7.74 (m, 2H), 7.64 (t, 1H), 7.57 (m, 2H), 7.32 (m, 2H), 6.82 (m,1H) ppm; LC-MS (ES+) 424.17 (M+H); HPLC-Method A, R_(t) 3.14 min.

Example 90(1H-Indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-90)

Prepared using THF as solvent to afford the title compound as a TFA salt(23% yield). HPLC-Method A, R_(t) 2.97 min (95%); ¹HNMR (DMSO-d6, 500MHz) δ 12.9 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m), 7.75-7.50 (8H,s), 7.30 (1H, m), 6.90 (1H, m), 4.0 (3H, s); MS (m/z) 436.2 (M+H).

Example 91(5-Fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-91)

Prepared using TFA as solvent to afford the title compound as a TFA salt(23% yield). HPLC-Method A, R_(t) 3.10 min. (99%); ¹HNMR (DMSO-d6, 500MHz): 13.0 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m), 7.75-7.50 (7H, m),7.35 (1H, m), 7.25 (1H, m), 4.0 (3H, s); MS (m/z) 454.2 (M+H).

Example 92(7-Fluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-92)

Prepared using THF as solvent to afford the title compound as a TFA salt(98 mg, 58% yield). HPLC-Method A, R_(t) 3.20 min (92%); ¹HNMR (DMSO-d6,500 MHz) δ 13.45 (1H, bs), 11.0-10.7(1H, bs), 8.25 (1H, m), 7.75-7.60(5H, m), 7.50 (1H, m), 7.40 (1H, m), 7.15 (1H, m), 6.95 (1H, m) 4.0 (3H,s); MS (m/z) 454.2 (M+H).

Example 93(5,7-Difluoro-1H-indazol-3-yl)-[8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-93)

Prepared using THF as solvent to afford the title compound as a TFA salt(36% yield). HPLC-Method A, R_(t) 3.27 min. (95%); ¹HNMR (DMSO-d6, 500MHz): 13.65 (1H, bs), 11.0-10.7(1H, bs), 8.22 (1H, m), 7.75-7.60 (5H,m), 7.40 (1H, m), 7.35 (1H, m), 7.19 (1H, m), 4.0 (3H, s); MS (m/z)472.2 (M+H).

Example 94[2-(2-Chloro-pyridin-3-yl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-94)

Prepared in DMF. ¹HNMR (500 MHz, DMSO-d6) δ 13.62 (br s, 1H, 11.06-10.71(m, 1H), 8.16-7.70 (m, 4H), 7.60-7.09 (m, 3H); LC-MS (ES+) 409.14 (M+H);HPLC-Method A, R_(t) 2.89 min.

Example 95[2-(2-Chloro-4-nitro-phenyl)-quinazolin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-95)

Prepared in THF. ¹HNMR (500 MHz, DMSO-d6) δ 13.35 (s, 1H), 10.74 (s,1H), 8.67 (d, J=8.4 Hz, 1H), 8.29 (d, J=2.05 Hz, 1H), 8.18-8.08 (m, 1H),8.07-7.60 (m, 4H), 7.53-7.10 (m, 2H). LC-MS (ES+) 453.15 (M+H);HPLC-Method D, R_(t) 3.63 min.

Example 96[2-(4-Amino-2-chloro-phenyl)-quinazolin-4-yl]-(5,7-Difluoro-1H-indazol-3-yl)-amine(II-96)

A solution of compound II-95 (8 mg, 0.018 mmol) and tin chloridedihydrate (22 mg, 0.1 mmol) in ethanol (2 mL) was heated at 100° C. for24 h. The reaction was diluted with EtOAc (10 mL), washed with 1N NaOHsolution (2×10 mL), brine, and dried over anhydrous sodium sulfate toafford the crude product. Purification was achieved by flashchromatography on silica gel (eluting with 1-3% MeOH in CH₂Cl₂.) Thetitle compound was isolated as pale yellow solid (1.2 mg, 16% yield).LC-MS (ES+) 423.12 (M+H), HPLC-Method C, R_(t) 13.78 min.

Example 97(4,5,6,7-Tetrahydro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-97)

Prepared in 34% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.58 (m, 2H), 1.66 (m,2H), 2.24 (m, 2H), 2.54 (m 2H), 7.63 (m, 3H), 7.71 (t, 1H), 7.75 (d,1H), 7.78 (d, 1H), 7.85 (t, 1H), 8.53 (d, 1H), 9.99 (s, 1H), 12.09 (s,1H); EI-MS 410.2 (M+1); HPLC-Method A, R_(t) 3.05 min.

Example 98(1H-Pyrazolo[4,3-b]pyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-98)

Prepared in DMF (37% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.1 (s, br, 1H), 11.2 (s, br, 1H), 8.73 (d, 1H), 8.54 (dd, 1H), 8.12(d, 1H), 8.06 (t, 1H), 7.90 (d, 1H), 7.84 (t, 1H), 7.75 (d, 1H), 7.69(m, 2H), 7.65 (t, 1H), 7.47 (dd, 1H) ppm; LC-MS (ES+) 407.18 (M+H);HPLC-Method A, R_(t) 2.77 min.

Example 99(1H-Pyrazolo[3,4-b]pyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-99)

Prepared in DMF (45% yield). ¹HNMR (500 MHz, DMSO-d6) δ 13.5 (s, br,1H), 11.3 (s, br, 1H), 8.78 (d, 1H), 8.49 (d, 1H), 8.17 (d, 1H), 8.03(t, 1H), 7.89 (d, 1H), 7.80 (m, 2H), 7.74 (m, 2H), 7.68 (m, 1H), 7.08(dd, 1H) ppm. MS (ES+) 407.16 (M+H), (ES−) 405.16 (M−H); HPLC-Method A,R_(t) 2.80 min.

Example 100(6-Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-100)

Prepared in DMF (11% yield). 1HNMR (500 MHz, DMSO-d6) δ 13.2 (s, br,1H), 10.8 (s, br, 1H), 8.57 (d, 1H), 7.95 (t, 1H), 7.82 (d, 1H), 7.72(t, 1H), 7.65 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H, buried by DMSO), 2.20(s, 3H) ppm. LC-MS (ES+) 435.22 (M+H), (ES−) 433.25 (M−H); HPLC-MethodA, R_(t) 2.94 min.

Example 101(6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amineII-101

Prepared in DMF (6% yield). ¹HNMR (500 MHz, DMSO-d6) δ 12.6 (s, 1H),11.0 (s, br, 1H), 8.60 (d, 1H), 7.95 (t, 1H), 7.88 (d, 1H), 7.80 (d,1H), 7.68 (m, 4H), 7.40 (s, 3H), 7.22 (s, 2H), 6.61 (s, 1H) ppm. LC-MS(ES+) 500.21 (M+H), (ES−) 498.16 (M−H); HPLC-Method A, R_(t) 3.00 min.

Example 103[6-Methyl-2-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(II-103)

MS 412.13 (M+H); HPLC-Method E R_(t) 1.248 min.

Example 104(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-amine(II-104)

MS 402.12 (M+H); HPLC-Method E, R_(t) 1.188 min.

Example 105[6-Ethyl-2-(2-trifluoromethoxy-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-105)

MS 364.14 (M+H); HPLC-Method E, R_(t) 1.112 min.

Example 106[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(II-106)

HNMR (500 MHz, DMSO) δ 12.23 (s, 1H), 10.78 (s, 1H), 7.73-7.47 (m, 7H),6.72 (s, 1H), 2.21 (s, 3H). MS: (M+H) 337.02. HPLC-Method A, R_(t) 2.783min.

Example 107(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-107)

Prepared in 68% yield. ¹HNMR (500 MHz, DMSO-d6)δ 2.16 (t, 2H), 2.88 (m,2H), 2.98 (t, 2H), 7.21 (td, 1H), 7.29 (dd, 1H), 7.50 (dd, 1H), 7.65 (t,1H), 7.67 (t, 1H), 7.73 (t, 1H), 7.79 (d, 1H), 10.22 (br. s, 1H), 12.99(br. s, 1H); EI-MS 414.2 (M+H); HPLC-Method A, R_(t) 2.92 min.

Example 108(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine(II-108)

HPLC-Method A, R_(t) 2.78 min. (95%); ¹HNMR (DMSO-d6, 500 MHz): 12.95(1H, bs), 11.45 δ 11.15(1H, bs), 9.20 (2H, m), 7.85-7.70 (2H, m),7.70-7.55 (4H, m), 7.50 (1H, m), 7.35 (1H, m), 7.05 (1H, m); MS (m/z)407.03 (M+H).

Example 109(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-amine(II-109)

Yellow, di-TFA salt (25% yield). HPLC (Method A) 3.10 min. (95%); ¹HNMR(DMSO-d6, 500 MHz): 13.8-13.6 (1H, bs), 11.4-11.2(1H, bs), 9.15 (2H, m),7.85-7.75 (2H, m), 7.75-7.62 (3H, m), 7.32 (2H, m); MS (m/z) 442.98(M+H).

Example 110[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-110)

Prepared from 2-aminonicotinic acid and 2-chlorobenzoyl chlorideafforded the title compound as a di-TFA salt (28% yield). HPLC-Method A,R_(t) 2.85 min. (95%); ¹HNMR (DMSO-d6, 500 MHz): 12.90 (1H, s),11.10-10.90 (1H, bs), 9.05 (2H, m), 7.75-7.60 (2H, m), 7.51 (1H, m),7.45-7.25 (5H, m), 6.95 (1H, m); MS (m/z) 372.99(M+H).

Example 111(5-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-111).

Prepared in 43% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H), 1.53 (m,2H), 1.77 (m, 4H), 2.95 (m, 2H), 3.04 (m, 2H), 7.22 (m, 2H), 7.50 (dd,1H), 7.72 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.05 (br s, 1H); EI-MS456.2 (M+H); HPLC-Method C, R_(t) 11.93 min.

Example 112[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-112)

Prepared in 67% yield. ¹HNMR (500MHz, DMSO-d6) δ 2.18 (m, 2H), 2.89 (m,2H), 3.02 (t, 2H), 7.24 (td, 1H), 7.42 (m, 2H), 7.49 (td, 1H), 7.52 (dd,1H), 7.54 (d, 1H), 7.57 (dd, 1H), 10.50 (br. s, 1H), 13.06 (br. s, 1H);EI-MS 380.1 (M+1); HPLC-Method C, R_(t) 9.68 min.

Example 113(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-113)

Prepared in 37% yield. ¹HNMR (500MHz, DMSO-d6) δ 2.65 (m, 2H), 2.85 (m,2H), 2.99 (t, 2H), 7.02 (t, 1H), 7.32 (t, 1H), 7.47 (d, 1H), 7.55 (d,1H), 7.68 (t, 1H), 7.74 (t, 1H), 7.80 (d, 1H), 10.37 (br. s, 1H), 12.91(br. s, 1H); EI-MS 396.1 (M+H); HPLC-Method B, R_(t) 9.88 min.

Example 114(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-114)

Prepared in 40% yield. ¹HNMR (500MHz, DMSO-d6) δ 2.15 (m, 2H), 2.87 (m,2H), 2.97 (t, 2H), 6.99 (td, 1H), 7.17 (dd, 1H), 7.38 (d, 1H), 7.65 (m,2H), 7.71 (t, 1H), 7.78 (d, 1H), 10.21 (br. s, 1H), 13.40 (br. s, 1H);EI-MS 414.1 (M+H); HPLC-Method C, R_(t) 9.99 min.

Example 115(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-amine(II-115)

Prepared according to Method C in 52% yield. ¹HNMR (500 MHz, DMSO-d6) δ2.16 (m, 2H), 2.89 (m, 2H), 2.97 (t, 2H), 7.19 (dd, 1H), 7.29 (td, 1H),7.63 (t, 1H), 7.66 (d, 1H), 7.71 (t, 1H), 7.78 (d, 1H), 10.16 (br. s,1H), 13.55 (br. s, 1H); EI-MS 432.1 (M+H); HPLC-Method C, R_(t) 10.09min.

Example 116[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-116)

Prepared in 56% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.16 (m, 2H), 2.85 (m,2H), 3.01 (t, 2H), 7.06 (t, 1H), 7.34 (t, 1H), 7.40 (t, 1H), 7.48 (m,2H), 7.53 (d, 1H), 7.56 (d, 1H), 7.63 (d, 1H), 10.39 (br. s, 1H), 12.91(s, 1H); EI-MS 362.1 (M+H); HPLC-Method A, R_(t) 3.09 min.

Example 117[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-117)

Prepared in 63% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.15 (m, 2H), 2.87 (m,2H), 3.00 (t, 2H), 7.01 (td, 1H), 7.19 (dd, 1H), 7.39 (t, 1H), 7.45 (m,2H), 7.51 (d, 1H), 7.55 (d, 1H), 10.35 (br. s, 1H), 13.45 (br. s, 1H);EI-MS 380.1 (M+H); HPLC-Method A, R_(t) R_(t) 3.15 min.

Example 118[2-(2-Chloro-phenyl)-6,7-dihydro-5H-cyclopentapyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-118)

Prepared in 60% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.18 (m, 2H), 2.91 (m,2H), 3.01 (t, 2H), 7.32 (t, 1H), 7.33 (td, 1H), 7.41 (t, 1H), 7.48 (t,1H), 7.53 (d, 1H), 7.55 (dd, 1H), 10.35 (br. s, 1H), 13.45 (br. s, 1H);EI-MS 398.1 (M+H); HPLC-Method A, R_(t) R_(t) 3.24 min.

Example 119(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-119)

Prepared in 36% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.47 (m, 2H), 1.53 (m,2H), 1.78 (m, 4H), 2.96 (m, 2H), 3.06 (t, 2H), 7.03 (t, 1H), 7.47 (t,1H), 7.72 (d, 1H), 7.73 (d, 1H), 7.72 (m, 3H), 7.81 (d, 1H), 10.52 (m,1H), 12.97 (br. s, 1H); EI-MS 438.2 (M+1); HPLC-Method A, R_(t) 3.37min.

Example 120(7-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-120)

Prepared in 40% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H), 1.52 (m,2H), 1.77 (m, 4H), 2.94 (m, 2H), 3.04 (m, 2H), 7.00 (td, 1H), 7.17 (dd,1H), 7.30 (d, 1H), 7.70 (m, 3H), 7.79 (d, 1H), 10.5 (m, 1H), 13.49 (brs, 1H); EI-MS 456.1 (M+H); HPLC-Method A, R_(t) 3.43 min.

Example 121(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidin-4-yl]-amine(II-121)

Prepared in 48% yield. ¹HNMR (500 MHz, DMSO-d6) δ 1.46 (m, 2H), 1.52 (m,2H), 1.77 (m, 4H), 2.95 (m, 2H), 3.03 (m, 2H), 7.14 (d, 1H), 7.30 (t,1H), 7.73 (m, 3H), 7.80 (d, 1H), 10.5 (m, 1H), 13.62 (br. s, 1H); EI-MS475.1 (M+1); HPLC-Method A, R_(t) 3.52 min.

Example 122[6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-122)

Prepared in 45% yield. ¹HNMR (500 MHz, CDCl3) δ 1.30 (2H, m), 1.46 (2H,m), 1.65 (2H, m), 1.76 (2H, m), 1.91 (2H, m), 2.61 (1H, br m), 7.08 (1H,t, J=7.4 Hz), 7.27 (1H, d, J=8.0 Hz), 7.35 (1H, t, J=7.1 Hz), 7.50 (1H,t, J=7.0 Hz), 7.58 (1H, t, J=7.4 Hz), 7.66 (3H, m), 7.72 (1H, d, J=7.8Hz), 8.0 (1H, br), 9.87 (1H, br) ppm; HPLC-Method D, R_(t) 3.57 min;LC-MS 438.17 (M+H)⁺

Example 123[6-(2-Fluoro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-123)

Prepared in 8% yield. ¹HNMR (500 MHz, CDCl₃) δ 7.18 (3H, m), 7.37 (1H,m), 7.43 (1H, t, J=7.9 Hz), 7.51 (1H, d, J=7.9 Hz), 7.55 (1H, t, J=7.6Hz), 7.65 (1H, t, J=7.4 Hz), 7.79 (1H, d, J=7.9 Hz), 7.85 (1H, d, J=7.6Hz), 8.19 (2H, m), 8.70 (1H, d, J=8.5 Hz) ppm; HPLC-Method D, R_(t) 4.93min; LC-MS 450.13 (M+H)⁺

Example 124(6-Fluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(II-124).

Prepared in DMF (87% yield) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ13.0 (s, 1H), 11.1 (s, br, 1H), 8.66 (d, 1H), 7.95 (t, 1H), 7.80 (d,1H), 7.72 (m, 2H), 7.62 (m, 4H), 7.21 (dd, 1H), 6.84 (td, 1H) ppm. LC-MS(ES+) 424.15 (M+H); HPLC-Method A, R_(t) 3.05 min.

Example 1253-[2-(2-Trifluoromethyl-phenyl)-quinazolin-4-ylamino]-1H-indazole-5-carboxylicacid methyl ester (II-125)

To a solution of compound II-79 (100 mg 0.21 mmol) in DMF (2 mL) wasadded MeOH (1 mL), DIEA (54 uL, 0.31 mmol) and PdCl₂(dppf) (4 mg, 0.005mmol). The flask was flushed with CO three times and then charged with aCO balloon. The reaction mixture was heated at 8° C. for 14 h thenpoured into water. The resulting precipitate was collected and washedwith water. The crude product was then purified first by flash column(silica gel, 50% ethyl acetate in hexanes) then by preparative HPLC toto afford II-125 (32%) as yellow solid. ¹HNMR (500 MHz, DMSO-d6) δ 13.3(s, 1H), 11.3 (s, br, 1H), 8.70 (d, 1H), 8.36 (s, 1H), 7.97 (t, 1H),7.82 (m, 2H), 7.71 (m, 3H), 7.58 (m, 2H), 7.51 (d, 1H), 3.75 (s, 3H)ppm; LC-MS (ES+) 464.13 (M+H); HPLC-Method A, R_(t) 3.12 min.

Example 208(5-Methyl-2H-pyrazol-3-yl)-[2-(2-naphthyl-1-yl)-quinazolin-4-yl]-amine(II-208)

¹HNMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.73 (m, 1H), 8.39 (m, 1H),8.09 (m, 2H), 7.95 (m, 3H), 7.62 (m, 3H), 6.78 (s, 1H), 2.32 (s, 3H); MS352.2 (M+H).

Example 209[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-214)

Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol).Purification by preparative HPLC afforded the title compound as ayellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, R_(t) 3.04 min;¹H NMR (DMSO, 500 MHz): δ 13.67 (1H, s), 11.40-11.25 (1H, bs), 9.35-9.25(2H, m), 7.95 (1H, m), 7.80-7.47 (5H, m), 7.35(1H, m), 7.15 (1H, m); MS(m/z), MH⁺ 391.1.

Example 210[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-215)

Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100mg, 0.36 mmol) and 5-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol).Purification by preparative HPLC afforded the title compound as ayellow, di-TFA salt (45 mg, 22% yield). HPLC-Method A, R_(t) 3.00 min;¹H NMR (DMSO, 500 MHz): δ 13.0 (1H, s), 10.90(1H, bs), 9.15-9.05 (2H,m), 7.70 (1H, m), 7.60-7.30 (6H, m), 7.20 (1H, m); MS (m/z), MH⁺ 391.1.

Example 211[2-(2-Chloro-phenyl)-pyrido[2,3-d]pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-216)

Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100mg, 0.36 mmol) and 7-Difluoro-1H-indazol-3-ylamine (112 mg, 0.66 mmol).Purification by preparative HPLC afforded the title compound as ayellow, di-TFA salt (130 mg, 62% yield). HPLC-Method A, R_(t) 3.12 min;¹H NMR (DMSO, 500 MHz): 13.80-13.60 (1H, bs), 11.30-11.10 (1H, bs),9.20-9.10 (2H, m), 7.80 (1H, m), 7.60-7.30 (6H, m); MS (m/z), MH⁺ 409.1.

Example 212[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(1H-indazol-3-yl)-amine(II-217)

Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100mg, 0.36 mmol) and 1H-indazol-3-ylamine (88 mg, 0.66 mmol). Purificationby preparative HPLC afforded the title compound as a yellow, di-TFA salt(72 mg, 33% yield). HPLC-Method A, R_(t) 3.21 min; ¹H NMR (DMSO, 500MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55(1H, m), 7.65 (1H, m), 7.55 (1H, m), 7.50-7.30 (5H, m), 7.00(1H, m); MS(m/z), MH⁺ 373.1.

Example 213[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(7-fluoro-1H-indazol-3-yl)-amine(II-218)

Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol).Purification by preparative HPLC afforded the title compound as ayellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, R_(t) 3.35 min;¹H NMR (DMSO, 500 MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s),8.75 (1H, m), 8.55 (1H, m), 7.70-7.35 (5H, m), 7.25(1H, m), 6.95 (1H,m),; MS (m/z), MH⁺ 391.08.

Example 214[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(II-219)

Prepared from 4-chloro-2-(2-chloro-5-fluoro-1H-indazol-3-ylamine (108mg, 0.72 mmol). Purification by preparative HPLC afforded the titlecompound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A,R_(t) 3.27 min; ¹H NMR (DMSO, 500 MHz): δ 13.05 (1H, s), 10.95 (1H, s),9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.60 (1H, m), 7.55 (1H, m),7.50-7.30 (5H, m), 7.25(1H, m); MS (m/z), MH⁺ 391.1.

Example 215[2-(2-Chloro-phenyl)-pyrido[3,4-d]pyrimidin-4-yl]-(5,7-difluoro-1H-indazol-3-yl)-amine(II-220)

Prepared from 4-chloro-2-(2-chloro-7-difluoro-1H-indazol-3-ylamine (112mg, 0.66 mmol). Purification by preparative HPLC afforded the titlecompound as a yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Method A,R_(t) 3.45 min; ¹H NMR (DMSO, 500 MHz): δ 13.65 (1H, s), 11.0 (1H, s),9.25 (1H, s), 8.80 (1H, m), 8.50 (1H, m), 7.60 (1H, m), 7.55 (1H, m),7.50-7.30 (5H, m); MS (m/z), MH⁺ 409.1.

Example 216 6-Fluoro-1H-indazol-3-ylamine (A1)

¹HNMR (500 MHz, DMSO-d6) δ 11.4 (s, 1H), 7.68 (dd, 1H), 6.95 (dd, 1H),6.75 (td, 1H), 5.45 (s, 2H) ppm; LC-MS (ES+) 152.03 (M+H); HPLC-MethodA, R_(t) 2.00 min.

Example 217 5-Fluoro-1H-indazol-3-ylamine (A2)

¹HNMR (500 MHz, DMSO-d6) δ 11.3 (s, 1H), 7.43 (d, 1H), 7.22 (m, 1H),7.08 (m, 1H), 5.29 (s, 2H) ppm; LC-MS (ES+) 152.01 (M+H); HPLC-Method A,R_(t) 1.93 min.

Example 218 5,7-Difluoro-1H-indazol-3-yl-amine (A3)

¹HNMR (500 MHz, CD₃OD) δ 7.22 (dd, J=2.0, 8.45 Hz, 1H), 7.04-6.87 (m,1H); LC-MS (ES+) 169.95 (M+H); HPLC-Method C, R_(t) 2.94 min

Example 219 7-Fluoro-1H-indazol-3-ylamine (A4)

¹HNMR (500 MHz, DMSO-d6) δ 11.8 (s, 1H), 7.42 (d, 1H), 6.97 (m, 1H),6.78 (m, 1H), 5.40 (s, 2H) ppm; LCMS (ES+) 152.01 (M+H); HPLC-Method A,R_(t) 2.00 min.

Example 220 7-Fluoro-6-trifluoromethyl-1H-indazol-3-ylamine (A5)

¹H-NMR (500 MHz, DMSO) δ 12.5 (s, 1H), 7.75 (d, 1H), 7.25 (m, 1H), 5.85(m, 1H) ppm; MS (FIA) 220.0 (M+H); HPLC-Method A, R_(t) 2.899 min.

Example 221 6-Bromo-1H-indazol-3-ylamine (A6)

¹H-NMR (500 MHz, DMSO) δ 11.5 (s, 1H), 7.65 (d, 1H), 7.40 (s, 1H), 7.00(d, 1H), 5.45 (br s, 1H) ppm; MS (FIA) 213.8 (M+H); HPLC-Method A, R_(t)2.441 min.

Example 222 4-Fluoro-1H-indazol-3-ylamine (A7)

¹H-NMR (500 MHz, DMSO) δ 11.7 (s, 1H), 7.17 (m, 1H), 7.05 (d, 1H), 6.7(br, 1H), 6.60 (dd, 1H), 5.20 (br s, 2H) ppm; MS (FIA) 152.0 (M+H);Method A, R_(t) 2.256 min.

Example 223 5-Bromo-1H-indazol-3-ylamine (A8)

¹H-NMR (500 MHz, DMSO) δ 11.55 (br s, 1H), 7.95 (s, 1H), 7.30 (d, 1H),7.20 (d, 1H), 5.45 (br s, 2H) ppm; MS (FIA) 213.8 (M+H); Method A, R_(t)2.451 min.

Example 224 5-Nitro-1H-indazol-3-ylamine (A9)

¹H-NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.20 (d, 1H), 7.45 (d, 1H),6.15 (br s, 1H) ppm; Method A, R_(t) 2.184 min

Example 225 4-Pyrrol-1-yl-1H-indazol-3-ylamine (A10)

¹H-NMR (500 MHz, DMSO) δ 7.20 (s, 2H), 7.00 (s, 2H), 6.75 (m, 1H), 6.25(s, 2H), 4.30 (d, 1H) ppm; Method A, R_(t) 2.625 min.

Example 2264-Chloro-5,6-dimethyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B1)

Prepared to afford a colorless oil in 75% yield. ¹H-NMR (500 MHz, CDCl3)δ 7.70 (d, J=7.8 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz,1H), 7.48 (t, J=7.5 Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H) ppm; MS (FIA)287.0 (M+H); HPLC-Method A, R_(t) 3.891 min.

Example 227 4-Chloro-2-(2-chloro-phenyl)-5,6-dimethyl-pyrimidine (B2)

Prepared to afford a yellow-orange oil in 71% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.73 (m, 1H), 7.52 (m, 1H), 7.39 (m, 2H), 2.66 (s, 3H), 2.45(s, 3H) ppm; MS (FIA) 253.0 (M+H); HPLC-Method A, R_(t) R_(t) 4.156 min.

Example 228 4-Chloro-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidine(B3)

Prepared to afford a pale yellow oil in 68% yield. ¹H-NMR (500 MHz,CDCl3) δ 7.72 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.57 (t, J=7.5Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.16 (s, 1H), 2.54 (s, 3H) ppm; MS(FIA) 273.0 (M+H); HPLC-Method A, R_(t) 3.746 min.

Example 2294-Chloro-6-cyclohexyl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B4)

Prepared to afford a yellow oil in 22% yield. ¹H-NMR (500 MHz, CDCl3) δ7.70 (m, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.19 (s,1H), 2.65 (m, 1H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5 (m, 2H), 1.3 (m, 2H),1.2 (m, 2H) ppm; MS (FIA) 341.0 (M+H).

Example 230 4-Chloro-6-phenyl-2-(2-trifluoromethyl-phenyl)-pyrimidine(B5)

Prepared to afford a yellow oil in 53% yield. ¹H-NMR (500 MHz, CDCl3) δ8.08 (dd, J=7.9, 1.6 Hz, 2H), 7.80 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.8 Hz,1H), 7.67 (s, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.47(m, 3H) ppm; MS (FIA) 335.0 (M+H); HPLC-Method A, R_(t) 4.393 min.

Example 231 4-Chloro-2-(2,4-dichloro-phenyl)-5,6-dimethyl-pyrimidine(B6)

Prepared to afford a white solid in 91% yield. ¹H-NMR (500 MHz, CDCl3) δ7.62 (d, J=8.3 Hz, 1H), 7.43 (d, J=7.0 Hz, 1H), 7.27 (dd, J=8.3, 2.0 Hz,1H), 2.55 (s, 3H), 2.35 (s, 3H) ppm; MS (FIA) 287, 289 (M+H);HPLC-Method A, R_(t) 4.140 min.

Example 2324-Chloro-6-(2-chloro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidine(B7)

Prepared to afford a yellow oil in 52% yield. ¹H-NMR (500 MHz, CDCl3) δ7.75 (m, 3H), 7.65 (m, 2H), 7.53 (m, 1H), 7.44 (m, 1H), 7.36 (m, 2H)ppm; MS (FIA) 369.1 (M+H); HPLC-Method A, R_(t) 4.426 min.

Example 2334-Chloro-6-(2-fluoro-phenyl)-2-(2-trifluoromethyl-phenyl)-pyrimidine(B8)

Prepared to afford a yellow oil in 95% yield. ¹H-NMR (500 MHz, CDCl3) δ8.24 (t, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.76 (d,J=8.0 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.43 (m,1H), 7.23 (t, J=7.6 Hz, 1H), 7.13 (m, 1H) ppm; MS (FIA) 353.0 (M+H).

Example 2344-Chloro-6-pyridin-2-yl-2-(2-trifluoromethyl-phenyl)-pyrimidine (B9)

Prepared to afford a pale yellow solid in 50% yield. ¹H-NMR (500 MHz,CDCl3) δ 8.68 (m, 1H), 8.48 (dd, J=7.9, 0.8 Hz, 1H), 8.38 (d, J=2.3 Hz,1H), 7.84 (m, 3H), 7.62 (t, J=7.6 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.38(m, 1H) ppm; MS (FIA) 336.0 (M+H); HPLC-Method A, R_(t) 4.575 min.

Example 2356-Benzyl-4-chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine(B1O)

¹HNMR (500 MHz, CDCl₃) δ 7.70 (d, 1H), 7.62 (d, 1H); 7.55 (t, 1H), 7.48(t, 1H), 7.32 (m, 4H), 7.25 (m, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.99(t, 2H), 2.80 (t, 2H) ppm; LCMS (ES+) 404.17 (M+H); HPLC-Method A, R_(t)3.18 min.

Example 2367-Benzyl-4-chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine(B11)

¹HNMR (500 MHz, CDCl₃) δ 7.69 (d, 1H), 7.60 (d, 1H), 7.54 (t, 1H), 7.47(t, 1H), 7.28 (m, 4H), 7.20 (m, 1H), 3.68 (s, 2H), 3.67 (s, 2H), 2.86(t, 2H), 2.79 (t, 2H) ppm. MS (ES+) 404.18 (M+H); HPLC-Method A, R_(t)3.12 min.

Example 237 4-Chloro-2-(4-fluoro-2-trifluoromethyl-phenyl)-quinazoline(B12)

¹HNMR (500MHz, CD₃OD) δ 8.43 (d, J=8.1 Hz, 1H), 8.20-8.05 (m, 2H),8.05-7.82 (m, 2H), 7.71-7.51 (m, 2H). LC-MS (ES+) 327.09 (M+H).HPLC-Method D, R_(t) 4.56 min.

Example 238 4-Chloro-2-(2-chloro-5-trifluoromethyl-phenyl)-quinazoline(B13)

LC-MS (ES+) 342.97 (M+H). HPLC-Method D, R_(t) 4.91 min.

Example 239 4-Chloro-2-(2-chloro-4-nitro-phenyl)-quinazoline (B14)

LC-MS (ES+) 319.98 (M+H). HPLC-Method D, R_(t) 4.45 min.

Example 240 4-Chloro-2-(2-trifluoromethyl-phenyl)-quinazoline (B15)

Prepared in 57% yield. White solid. ¹HNMR (500 MHz, DMSO-d6) δ 7.79 (t,1H), 7.86 (t, 1H), 7.94 (m, 3H), 8.15 (dd, 1H), 8.20 (td, 1H), 8.37 (m,1H); EI-MS 308.9 (M).

Example 2414-Chloro-2-(2-trifluoromethyl-phenyl)-6,7-dihydro-5H-cyclopentapyrimidine(B16)

Prepared in 22% yield. ¹HNMR (500 MHz, DMSO-d6) δ 2.19 (m, H), 3.01 (t,2H), 3.08 (t, 2H), 7.49 (t, 1H), 7.55 (t, 1H), 7.62 (d, 1H), 7.71 (d,1H). EI-MS 299.0 (M+H).

Example 2424-Chloro-2-(2-chloro-phenyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidine(B17)

Prepared according to Method C in 82% yield to afford a white solid.¹HNMR (500 MHz, CDCl₃) δ 1.67 (m 4H), 1.87 (m 2H), 3.02 (m 4H), 7.28 (m,2H), 7.40 (m, 1H), 7.65 (m, 1H); EI-MS 293.0 (M+1).

Example 2434-Chloro-2-(2-trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydro-cyclooctapyrimidine(B18)

Prepared in 38% yield to afford a brown oil. ¹HNMR (500 MHz, CDCl₃) δ1.35 (m 2H), 1.41 (m 2H), 1.76 (m 4H), 2.96 (m, 4H), 7.48 (t, 1H), 7.56(t, 1H), 7.66 (d, 1H), 7.70 (d, 1H); EI-MS 341.0 (M+1).

Example 244 4-Chloro-8-methoxy-2-(2-trifluoromethyl-phenyl)-quinazoline(B19)

Prepared from 8-methoxy-2-(2-trifluoromethyl-phenyl)-3H-quinazolin-4-one(1.0 g, 3.12 mmol), triethylamine hydrochloride (472 mg, 3.43 mmol), andPOCl₃. Purification by flash chromatography afforded a white solid (89%yield). HPLC-Method A, R_(t) 4.10 min, (98%), MS (m/z) 258.08 (M+H).

Example 245 2-(4-Chloro-quinazolin-2-yl)-benzonitrile (B20)

Prepared to afford a yellow solid in 1.5% yield. ¹H-NMR (500 MHz, CDCl3)δ 8.47 (d, 1H), 8.24 (d, 1H), 8.16 (d, 1H), 8.07 (impurity), 7.94 (t,1H), 7.92 (impurity), 7.86 (d, 1H), 7.68 (m, 2H), 7.65 (impurity), 7.54(impurity), 7.49 (t, 1H), 4.2 (impurity), 1.05 (impurity) ppm; MS(LC/MS) 266.05 (M+H); HPLC-Method A, R_(t) 3.88 min.

Example 246 6-Methyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one(D3)

Prepared to afford a yellow solid in 50% yield. ¹H-NMR (500 MHz,DMSO-d6) δ 12.7 (br s, 1H), 7.9 (m, 1H), 7.8 (m, 2H), 7.7 (m, 1H), 6.3(s, 1H), 2.21 (s, 3H) ppm; MS (FIA) 255.0 (M+H); HPLC-Method A, R_(t)2.578 min.

Example 247 6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-3N-pyrimidin-4-one(D4)

Prepared to afford an off-white solid in 54% yield. ¹H-NMR (500 MHz,DMSO-d6) δ 12.9 (br s, 1H), 7.9 (m, 4H), 6.3 (s, 1H), 2.5 (m, 1H), 1.9(m, 5H), 1.4 (m, 5H) ppm; MS (FIA) 323.1 (M+H); HPLC-Method A, R_(t)3.842 min.

Example 248 2-(2-Chloro-5-trifluoromethyl-phenyl)-3H-quinazoli-4-one(D10)

¹HNMR (500MHz, CD₃OD) δ 8.32-8.25 (m, 1H), 8.01 (s, 1H), 7.91-7.72 (m,1H), 7.66-7.55 (m, 1H). LC-MS (ES+) 325.01 (M+H). HPLC-Method D, R_(t)3.29 min.

Example 249 2-(4-Fluoro-2-trifluoromethyl-phenyl)-3H-quinazolin-4-one(D14)

¹HNMR (500 MHz, CD₃OD) δ 8.28 (d, 8.0 Hz, 1H), 7.94-7.84 (m, 1H),7.84-7.77 (m, 1H), 7.76-7.67 (m, 2H), 7.65-7.53 (m, 2H). LC-MS (ES+)309.06 (M+H). HPLC-Method D, R_(t) 2.88 min.

Example 250 2-(4-Nitro-2-chloro-phenyl)-3H-quinazolin-4-one (D15)

LC-MS (ES+) 302.03 (M+H). HPLC-Method D, R_(t) 2.81 min.

Example 251 2-(5-Fluoro-2-trifluoromethyl-phenyl)-3H-quinazolin-4-one(D17)

HNMR (500 MHz, CD₃OD) δ 8.28 (d, R_(t) J=8.05 Hz, 1H), 7.96 (dd, J=5.05,8.55 Hz, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.78-7.69 (m,1H), 7.66-7.46 (m,3H). LC-MS (ES+) 309.14 (M+H). HPLC-Method D, R_(t) 2.90 min.

Example 252 (1H-Indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-1)

Prepared by Method A in DMF to afford 70 mg (50% yield) as pale yellowsolid. ¹H NMR (500 MHz, DMSO-d6) δ 13.1 (s, br, 1H), 8.48 (d, 1H), 7.91(d, 2H), 7.76 (br, 2H), 7.45 (m, 2H), 7.36 (d, 1H), 7.20 (m, 4H), 6.86(t, 1H) ppm. MS (ES+) 338.07 (M+H); (ES−) 336.11 (M−H); HPLC-Method A,R_(t) 2.88 min.

Example 253(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-amine(III-7)

Prepared according to Method A. ¹H NMR (500 MHz, DMSO-d6) δ 12.1 (s, br,1H), 8.70 (s, br, 1H), 8.37 (d, J=6.7 Hz, 2H), 7.54 (m, 3H), 6.67 (s,1H), 2.82 (m, 2H), 2.68 (m, 2H), 2.37 (s, 3H), 1.90 (s, br, 4H); MS306.1 (M+H).

Example 254(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl)-amine(III-8): MS 320.48 (M+H); HPLC-Method E, R_(t) 1.124 min. Example 255(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-9)

Yellow solid, mp 286-289° C., ¹H NMR (DMSO) δ 2.35 (3H, s), 6.76 (1H,s), 7.61 (1H, m), 7.89 (2H, m), 8.32 (2H, d), 8.70 (1H, d), 8.78 (2H,d), 10.56 (1H, br s), 12.30 (1H, br s); IR (solid) 1620, 1598, 1571,1554, 1483, 1413, 1370, 1328; MS 303.2 (M+H)⁺

Example 256(7-Chloro-2-pyridin-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-28)

¹H NMR (DMSO-d6) δ 2.35 (3H,s), 6.75 (1H, s), 7.65 (1H, d), 7.93 (1H,s), 8.30 (2H, d), 8.73 (1H, d), 8.79 (2H, d), 10.69 (1H, s), 12.33 (1H,s); MS m/z 337.2 (M+H)⁺.

Example 257(6-Chloro-2-pyridin-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(111-29)

¹H NMR (DMSO-d6) δ 2.31 (3H, s), 6.74 (1H,s), 7.89 (1H, s), 8.30 (2H,d), 8.80 (2H, d), 8.91 (1H, s), 10.63 (1H, s), 12.29 (1H, s); MS 337.2(M+H)⁺.

Example 258(2-Cyclohexyl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (III-30)

¹H NMR (DMSO) δ 2.35 (3H, s), 1.70 (3H, m), 1.87 (2H, d), 1.99 (2H, d),2.95 (1H, t), 6.72 (1H, s), 7.75 (1H, d), 7.88 (1H, s), 7.96 (1H, s),8.83 (1H, s), 11.95 (1H, s), 12.70 (1H, s); MS 308.4 (M+H)⁺.

Example 259 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-31)

mp 246° C.; ¹H NMR (400 MHz) δ 2.35 (3H, s), 6.70 (1H, br s), 7.51-7.57(4H, m), 7.83-7.84 (2H, d), 8.47-8.50 (2H, d), 8.65 (1H, d), 10.4 (1H,s), 12.2 (1H, bs); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1(M+H)+.

Example 260[2-(4-lodophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-32)

¹H NMR (DMSO-d6) δ 2.34 (3H, s), 6.72 (1H, s), 7.56 (1H, d), 7.84 (2H,d), 7.93 (2H, d), 8.23 (2H, d), 8.65 (1H, s), 10.44 (1H, s), 12.24 (1H,s); MS 428.5 (M+H)+.

Example 261[2-(3,4-Dichlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-33)

A suspension of 2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1 g, 3.43mmol) in phosphorus oxychloride (4 mL) was stirred at 110° C. for 3hours. The solvent was removed by evaporation and the residue is treatedcarefully with cold aqueous, saturated NaHCO₃. The resulting solid wascollected by filtration and washed with ether toafford-4-chloro-2-(3,5-dichloro-phenyl)-quinazoline as a white solid(993 mg, 93%). To the above compound (400 mg, 1.29 mmol) in THF (30 mL)was added 3-amino-5-methyl pyrazole (396 mg, 2.58 mmol) and theresulting mixture heated at 65° C. overnight. The solvents wereevaporated and the residue triturated with ethyl acetate, filtered, andwashed with the minimum amount of ethanol to afford compound III-33 as awhite solid (311 mg 65%): mp 274° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.69(1H, s), 7.60 (1H, m), 7.84 (1H, d), 7.96 (2H, d), 8.39 (1H, dd), 8.60(1H, d), 8.65 (1H, d), 10.51 (1H, s), 12.30 (1H, s); IR (solid) 1619,1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5(M+H)⁺.

Example 262[2-(4-Bromophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34)

mp 262-265° C.; ¹H NMR (DMSO) δ 2.34 (3S, s), 6.73 (1H, s), 7.55 (1H,m), 7.74 (2H, d), 7.83 (2H, m), 8.40 (2H, d), 8.65 (1H, d), 10.44 (1H,s), 12.25 (1H, s); IR (solid) 1603, 1579, 1546, 1484, 1408, 1365; MS380.1/382.1 (M+H)+.

Example 263[2-(4-Chlorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-35)

mp >300° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.74 (1H, s), 7.53-7.62 (3H,m), 7.84 (2H, d), 8.47 (2H, d), 8.65 (1H, d), 10.44 (1H, s), 12.26 (1H,s); IR (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2(M+H)+.

Example 264[2-(3,5-Dichlorophenyl)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-36)

mp 228° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.69 (1H, s), 7.96 (1H, d),8.21 (3H, m), 8.56 (1H, d), 8.60 (2H, d), 10.51 (1H, s), 12.30 (1H, s);IR (solid) 1546, 1331, 802, 763, 729, 658, 652; MS 370.5 (M+H)+.

Example 265[2-(4-Cyanophenyl)-quinazolin-4-yl-(5-methyl-2H-pyrazol-3-yl)-amine(III-37)

mp 263° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 6.72 (1H, s), 7.61 (1H, d),7.88 (2H, s), 8.04 (2H, d), 8.63 (2H, d), 8.67 (1H, s), 10.52 (1H, s),12.27 (1H, s); IR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2 (M+H)+.

Example 266[2-(3-lodophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-38)

mp 234-235° C.; ¹H NMR (DMSO) δ 2.35 (3H, s), 6.73 (1H, s), 7.35 (1H,m), 7.56 (1H, m), 7.85 (3H, m), 8.47 (1H, m), 8.65 (1H, m), 8.86 (1H,s), 10.49 (1H, s), 12.28 (1H, br s); IR (solid) 1560, 1541, 1469, 1360;MS 428.1 (M+H)+.

Example 267[2-(4-Ethylsulfanylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-39)

mp 229-231° C.; ¹H NMR (DMSO) δ 1.29 (3H, t), 2.35 (3H, s), 3.07 (2H,q), 6.76 (1H, s), 7.43 (2H, d), 7.51 (1H, m), 7.81 (2H, m), 8.41 (2H,d), 8.64 (1H, d), 10.38 (1H, s), 12.24 (1H, br s); IR (solid) 1587,1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 (M+H)+.

Example 268(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-40)

mp 218-219° C.; ¹H NMR (DMSO-d6) δ 0.70-0.80(2H, m), 0.90-1.00 (2H, m),6.70 (1H, s), 7.45-7.55 (4H, m), 7.80-7.85 (2H, m), 8.45-8.55 (2H, m),8.65 (1H, d), 10.40 (1H, s), 12.27 (1H, s); IR (solid) 1624, 1605, 1591,1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, 828, 803, 780, 762,710; MS 328.2 (M+H)⁺.

Example 269[2-(4-tert-Butylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-41)

mp >300° C.; ¹H NMR (DMSO-d6) δ 1.35 (9H, s), 2.34 (3H, s), 6.79 (1H,s), 7.55 (3H, d), 7.85 (2H, d), 8.39 (2H, d), 8.62 (1H, d), 10.35 (1H,s), 12.22 (1H, s); IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409,1371, 1359, 998, 841, 825, 766, 757; MS 358.3 (M+H)⁺.

Example 270[2-(4-Chlorophenyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(III-42)

¹H NMR (DMSO-d6) δ 0.77 (4H, br m),2.05 (1H, m), 6.59 (1H, s), 7.60 (1H,d), 7.85 (2H, d), 7.91 (2H, d), 8.22 (2H, d), 8.65 (1H, s), 10.51(1H,s), 12.33 (1H,s); MS 362.1 (M+H)⁺.

Example 271(2-Benzo[1,3]dioxol-5-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-43)

¹H NMR (DMSO) δ 2.33 (3H, s), 6.13 (2H, s), 6.78 (1H,s), 7.11 (1H, d),7.80 (1H, t), 7.94 (1H, s), 8.09 (3H, m), 8.25 (1H, d), 10.34 (1H, s),12.21 (1H, s); MS 346.5 (M+H)⁺.

Example 272[2-(4-Dimethylaminophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-44)

¹H NMR (DMSO-d6) δ 2.02 (6H, s), 2.39 (3H, s), 6.83 (1H, s), 7.71 (1H,d), 7.98 (2H, s), 8.04 (2H, d), 8.33 (2H, d), 8.67 (1H, s), 11.82 (1H,s), 12.72 (1H, s); MS 345.3 (M+H)⁺.

Example 273[2-(3-Methoxyphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-45)

mp 226° C.; ¹H NMR (DMSO) δ 2.34 (3H,s), 3.92 (3H, s), 6.72 (1H, s),7.21 (1H, d), 7.57 (1H, t), 7.79 (1H, t), 8.02 (3H, m), 8.14 (1H, s),8.79 (1H, d), 10.39 (1H,s), 12.22 (1H, s); IR (solid) 1599, 1572, 1538,1478, 1427, 1359, 833, 761, 661; MS 332.2 (M+H)⁺.

Example 275(5-Cyclopropyl-2H-pyrazol-3-yl)-t2-(3,4-dichlorophenyl)-quinazolin-4-yl]-amine(III-46)

¹H NMR (DMSO-d6) δ 0.86 (2H, d), 1.02 (2H, d), 1.69 (1H, m), 6.56 (1H,s), 7.57 (1H, d), 7.84 (4H, m), 8.40 (1H, d), 8.58 (1H, s), 8.64 (1H,s), 10.53 (1H, s), 12.36 (1H, s); MS 396.0 (M+H)⁺.

Example 276(2-Biphenyl-4-yl-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(III-47)

To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34) (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol)in THF:water (1:1, 4 mL) was added Na₂CO₃ (219 mg, 2.06 mmol),triphenylphosphine (9 mg, 1/15 mol %) and palladium acetate (1 mg, 1:135mol %). The resulting mixture was heated at 80° C. overnight, thesolvents were evaporated and the residue purified by flashchromatography (gradient of dichloromethane:MeOH) to afford III-21 as ayellow solid (99 mg, 51%): ¹H NMR (DMSO) δ 2.37 (3H, s), 6.82 (1H, s),7.39-7.57 (4H, m), 7.73-7.87 (6H, m), 8.57 (2H, d), 8.67 (1H, d), 10.42(1H, s), 12.27 (1H, s); MS 378.2 (M+H)⁺.

Example 277[2-(4-Ethynylphenyl)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-48)

To a mixture of[2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5mmol)in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol %), Pd(PPh₃)₂Cl₂ (4.2mg, 1:50 mol %) and triethylamine (121 mg, 0.36 mmol). The resultingmixture was heated at 120° C. overnight and the solvent evaporated. Theresidue was triturated in ethyl acetate and the resulting precipitatecollected by filtration. The collected solid was suspended in THF (3 mL)and TBAF (1M in THF, 1.1 eq) was added. The reaction mixture was stirredat room temperature for 2 hours and the solvent evaporated. The residuewas purified by flash chromatography (silica gel, gradient of DCM:MeOH)to afford III-48 as a white solid (68 mg, 70%): ¹H NMR (DMSO) δ 2.34(3H, s), 4.36 (1H, s), 6.74 (1H_(,) s), 7.55 (1H, m), 7.65 (2H, d), 7.84(2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS326.1 (M+H)⁺.

Example 278[2-(3-Ethynylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-49)

mp 204-207° C.; ¹H NMR (DMSO) δ 2.34 (3H, s), 4.28 (1H, s), 6.74 (1H,s), 7.55-7.63 (3H, m), 7.83-7.87 (2H, m), 8.49 (1H, d), 8.57 (1H, s),8.65 (1H, d), 10.46 (1H, s), 12.27 (1H, s); IR (solid) 1598, 1574, 1541,1489, 1474, 1422, 1365; MS 326.1 (M+H)+.

Example 279[2-(3-Methylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-50)

A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POCl₃(60 mL, 644 mmol) and N,N-dimethylaniline (8 mL, 63.1 mmol) was heatedunder reflux for 2 h. The excess POCl₃ was removed in vacuo, the residuepoured into ice, and the resulting precipitate collected by filtration.The crude solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) waswashed with water and dried under vacuum for next step use withoutfurther purification. To a solution of the 2,4-dichloro-quinazoline (3.3g, 16.6 mmol) in anhydrous ethanol (150 mL) was added5-methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol)and the resultingmixture was stirred at room temperature for 4 hours. The resultingprecipitate was collected by filtration, washed with ethanol, and driedunder vacuum to afford 4.0 g (93% yield) of(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which wasused in the next step without further purification. To a solution of the(2-chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2MNa₂CO₃ (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). The flask wasflushed with nitrogen and the catalyst PdCl₂(dppf) (0.011 mmol) added inone portion. The reaction mixture was then heated at 80° C. for 10hours, cooled to room temperature, and poured into water (2 mL). Theresulting precipitate was collected by filtration, washed with water,and purified by HPLC to afford III-50 as a pale yellow solid (61 mg,75%): ¹H NMR (500 MHz, DMSO-d6) δ 12.3 (br s, 1H), 10.4 (br s, 1H), 8.75(d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.78 (s, 2H), 7.55 (m, 1H), 7.45(m, 1H), 7.35 (m, 1H), 6.80 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H); MS316.1 (M+H).

Example 280[2-(3,5-Difluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-51)

¹H NMR (500 MHz, DMSO-d6) δ 12.3 (br s, 1H), 10.8 (br s, 1H), 8.63 (d,1H), 7.95 (d, 2H), 7.85 (m, 2H), 7.58 (t, 1H), 7.41 (t, 1H), 6.59 (s,1H), 2.27 (s, 3H); MS 338.1 (M+H).

Example 281[2-(3-Chloro-4-fluorophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-52)

¹H NMR (500 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.8 (br s, 1H), 8.65 (d,1H), 8.50 (d, 1H), 8.36 (m, 1H), 7.85 (m, 1H), 7.60 (m, 1H), 6.62 (s,1H), 2.30 (s, 3H); MS 354.1 (M+H).

Example 282(5-Methyl-2H-pyrazol-3-yl)-[2-(3-trifluoromethylphenyl)-quinazolin-4-yl]-amine(III-53)

¹H NMR (500 MHz, DMSO-d6) δ 12.2 (br, 1H), 10.45(br, 1H), 7.53 (s, 1H),7.43 (d, J=7.2 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.65 (d, J=8.3 Hz, 1H),6.57 (t, J=7.6 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 6.43 (t, J=7.8 Hz, 1H),6.32 (t, J=7.6 Hz, 1H), 5.51 (s, 1H), 2.03 (s, 3H); MS 370.2 (M+H).

Example 283[2-(3-Cyanophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-54)

¹H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.96 (m, 2H), 8.28 (d, J=7.3Hz, 1H), 8.16 (s, br, 2H), 8.06 (t, J=7.8 Hz, 1H), 7.88 (m, 1H), 6.96(S, 1H), 2.58 (s, 3H); MS 327.1 (M+H).

Example 284[2-(3-Isopropylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-55)

¹H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=7.5 Hz, 1H), 8.37 (s, 1H), 8.26(s, 1H), 8.08 (m, 2H), 7.81 (t, br, 1H), 7.67 (m, 2H), 6.88 (s, 1H),3.12 (m, 1H), 2.40 (s, 3H), 1.38 (d, J=6.9 Hz, 6H); MS 344.2 (M+H).

Example 285(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-3-yl-quinazolin-4-yl)-amine(III-56)

¹H NMR (500 MHz, DMSO-d6) 89.50 (s, 1H), 8.84 (d, J=7.3 Hz, 1H), 8.80(d, J=4.4 Hz, 1H), 8.66 (d, J=8.2 Hz, 1H), 7.87 (m, 2H), 7.77 (m, 1H),7.60 (t, J=7.2 Hz, 1H), 6.67 (s, 1H), 2.28 (s, 3H); MS 303.1 (M+H).

Example 286[2-(3-Acetylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-57)

¹H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.55 (d, J=7.7 Hz, 1H), 8.42(d, J=7.6 Hz, 1H), 8.00 (d, J=7.0 Hz, 1H), 7.76 (m, 2H), 7.58 (t, J=7.7Hz, 1H), 7.48 (s, br, 1H), 6.60 (s, 1H), 2.49 (s, 3H), 2.03 (s, 3H); MS344.1 (M+H).

Example 287[2-(3,5-Ditrifluoromethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-58)

¹H NMR (500 MHz, DMSO-d6) δ 10.7 (s, br, 1H), 8.95 (s, 2H), 8.63 (d,J=8.2 Hz, 1H), 8.25 (s, 1H), 7.86 (m, 2H), 7.58 (t, J=6.9 Hz, 1H), 6.62(s, 1H), 2.26 (s, 3H); MS 438.1 (M+H).

Example 288[2-(3-Hydroxymethylphenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-59)

¹H NMR (500 MHz, DMSO-d6) δ 8.74 (d, J=7.9 Hz, 1H), 8.33 (s, 1H), 8.17(s, br, 1H), 7.95 (s, br, 1H), 7.89 (s, br, 1H), 7.62 (m, 3H), 6.72 (s,1H), 5.53 (s, 1H), 4.60 (s, 2H), 2.28 (s, 3H); MS 332.1 (M+H).

Example 289(5-Methyl-2H-pyrazol-3-yl)-[2-(3-phenoxyphenyl)-quinazolin-4-yl]-amine(III-60)

mp 231-232° C.; ¹H NMR (DMSO-d6) δ 2.21 (3H, s), 6.59 (1H, s), 7.10-7.22(4H, m), 7.41-7.45 (2H, m), 7.54-7.59 (2H, m), 7.81 (2H, s), 8.09 (1H,s), 8.27 (1H, m), 8.64 (1H, m), 10.40 (1H, s), 12.20 (1H, s); IR(solid); IR (solid) 1589, 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7(M+H)⁺.

Example 290(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-phenoxyphenyl)-quinazolin-4-yl]-amine(III-61)

mp 193-195° C.; ¹H NMR (DMSO-d6) δ 0.67 (2H, m), 0.93 (2H, m),1.87(1H,m), 6.56 (1H, s), 7.06-7.20 (4H, m), 7.40-7.43 (2H, m), 7.55-7.59(2H, m), 7.81 (2H, s), 8.11 (1H, s), 8.27 (1H, m), 8.63 (1H, m), 10.43(1H, s), 12.26 (1H, s); IR (solid); IR (solid) 1589, 1574, 1527, 1483,1369, 1226; MS 420.7 (M+H)⁺.

Example 291(5-Methyl-2H-pyrazol-3-yl)-(2-thiophen-3-yl-quinazolin-4-yl)-amine(III-62)

¹H NMR (500 MHz, DMSO-d6) δ 11.78 (s, br, 1H), 8.75 (d, J=8.1 Hz, 1H),8.68 (s, 1H), 7.98 (dd, J=7.9, 7.5 Hz, 1H), 7.89 (m, 2H), 7.81 (m, 1H),7.68 (t, J=7.5 Hz, 1H), 6.69 (s, 1H), 2.30 (s, 3H); MS 308.1 (M+H)

Example 292 (2-Phenyl-quinazolin-4-yl)-(2H-pyrazol-3-yl)-amine (III-63)

mp 247-249° C.; ¹H NMR (DMSO) δ 6.99 (1H, br s), 7.49-7.58 (5H, m), 7.81(1H, br s), 7.83 (2H, m), 8.47-8.49 (2H, m), 8.66 (1H, d), 10.54 (1H,s), 12.59 (1H, s); IR (solid) 3145, 2922, 1622, 1597; MS 288.2 (M+H)⁺.

Example 293 (2H-Pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-64)

mp 285-286° C.; ¹H NMR (DMSO) δ 6.99 (1H, br s), 7.65 (1H, m), 7.81-7.94(3H, m), 8.3-8.35 (2H, m), 8.73 (1H, d), 8.84-8.90 (2H, m), 10.76 (1H,s), 12.6 (1H, S); IR (solid) 3180, 2972, 1600, 1574; MS 289.2 (M+H)⁺.

Example 294 5-Ethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-65)

mp 221-222° C.; ¹H NMR (DMSO) δ 1.31 (3H, t), 2.68 (2H, d), 6.80 (1H,s), 7.50-7.60 (4H, m), 8.45-8.55 (2H, m), 8.65-8.75 (1H, m), 10.44(1H,s), 12.27 (1H,s); IR (solid) 3190, 1622, 1595, 1575, 1533, 1482,1441, 1420, 1403, 1361, 758, 711; MS 316.2 (M+H)⁺.

Example 295 (2-Phenyl-quinazolin-4-yl)-(5-propyl-2H-pyrazol-3-yl)-amine(III-66)

mp 204-205° C.; 1H NMR (DMSO-d6) δ 1.02 (3H, t), 1.66-1.75 (2H, m), 2.69(2H, t), 6.80 (1H, s), 7.45-7.60 (4H,m), 7.80-7.88 (2H, m), 8.45-8.50(2H, m), 8.65 (1H, d), 10.39 (1H, s), 12.25 (1H, s); IR (solid) 1621,1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827, 808, 763, 709,697; MS 330.2 (M+H)⁺.

Example 296(5-Isopropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-67)

mp 218-219° C.; ¹H NMR (DMSO-d6) δ 1.36 (6H, d), 3.05 (1H, m), 6.86 (1H,s), 7.48-7.59 (4H, m), 7.80-7.88 (2H, m), 8.49-8.58 (2H, m), 8.66 (1H,d), 10.47 (1H, s), 12.30 (1H, s); IR (solid) 3173, 2968, 1619, 1593,1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707,666, 659; MS 330.2 (M+H)⁺.

Example 297(5-tert-Butyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-68)

mp 136-137° C.; ¹H NMR (DMSO-d6) δ 1.38 (9H, s), 6.87 (1H, br s),7.51-7.57 (4H, m), 7.84-7.85 (2H, m), 8.49-8.51 (2H, m), 8.65 (1H, d),10.43 (1H, s), 12.21 (1H, br s); IR (solid) 3162, 2963, 1621, 1590,1572; MS 344.2(M+H)⁺.

Example 298(5-tert-Butyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-quinazolin-4-yl)-amine(III-69)

mp>300° C.; ¹H NMR (DMSO) δ 1.38 (9H, s), 6.82 (1H, br s), 7.63 (1H, m),7.86-7.91 (2H, m), 8.32-8.33 (2H, d), 8.69 (1H, d), 8.75-8.76 (2H, d),10.60 (1H, s), 12.31 (1H, br s); IR (solid) 3683, 3149, 2963, 1621; MS345.2(M+H)⁺.

Example 299(5-Cyclopentyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-70)

mp 240-241° C.; ¹H NMR (DMSO-d6) δ 1.68-1.89 (6H, m), 2.03-2.17 (2H, m),3.14-3.22 (1H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.89 (2H, m),8.45-8.52 (2H, m), 8.67 (1H, d), 10.52 (1H, s), 12.26 (1H, s); IR(solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325, 999,951, 801, 775, 761, 747, 710695, 668, 654; MS 356.2(M+H)+.

Example 300 (5-Phenyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-71)

mp 207-209° C.; ¹H NMR (DMSO) δ 7.38-7.40 (1H, m), 7.50-7.58 (6H, m),7.82-7.88 (4H, m), 8.51 (2H, m), 8.67 (1H, s), 10.58 (1H, s), 13.11 (1H,br s); IR (solid) 3345, 3108, 1627, 1612; MS 364.2 (M+H)⁺.

Example 301 (5-Carboxy-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-72)

(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73) (345 mg, 1 mmole in THF, 6 mL) was treated with NaOH (1M, 4.0mL), stirred at 50° C. for 5 hours, cooled to room temperature, andneutralised with 1M HCl. The mixture was concentrated in vacuo to removeTHF then diluted with water and the resulting precipitate filtered. Theresidual solid was dried at 80° C. under vacuum to afford III-72 as anoff-white solid (312 mg, 94%): mp 289-291° C. (dec.); ¹H NMR (DMSO) δ7.45 (1H, br s), 7.50-7.60 (5H, m), 7.80-7.88 (2H, m), 7.40-7.50 (2H,m), 8.60-8.70 (1H, d), 10.70 (1H, s), 13.00-13.80 (2H, br s); IR (solid)1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004,827, 764, 705; MS 332.3(M+H)⁺.

Example 302(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73)

mp 271-273° C.; ¹H NMR (DMSO) δ 3.95 (3H, s), 7.50-7.65 (5H, m),7.80-7.98 (2H, m), 8.40-8.50 (2H, m), 8.65-8.73 (1H, m), 10.80 (1H, s),13.80 (1H, s); IR (solid) 3359, 1720, 1624, 1597, 1561, 1538, 1500,1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944,827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H)⁺.

Example 303(5-Hydroxymethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-74)

A solution of(5-Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-73) (345 mg, 1 mmol) in anhydrous THF (10 mL) was treated withlithium borohydride (125 mg, 5.75 mmol) at 65° C. for 5 hours. Themixture was cooled to room temperature then combined with 2M HCl andethyl acetate. Solid sodium hydrogen carbonate was added to achieve pH 8and the resulting mixture extracted with ethyl acetate. The extractswere dried over magnesium sulphate and concentrated. Purification byflash chromatography (SiO₂, methanol-dichloromethane gradient) affordedIII-74 (95 mg, 30%) as an off-white solid: mp 238-239° C.; ¹H NMR (DMSO)δ 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, s), 7.50-7.60 (4H, m),7.85-7.90 (2H, m), 8.48-8.54 (2H, m), 8.69 (1H, 1H), 10.40 (1H, s),12.48 (1H, s); IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532,1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793, 780,7124; MS 318.2(M+H)⁺.

Example 304(5-Methoxymethyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-75)

mp 190-191° C.; ¹H NMR (DMSO) δ 3.34 (3H, s), 4.45 (2H, s), 7.00 (1H,s), 7.50-7.62 (4H, m), 7.82-7.90 (2H, m), 8.45-8.52 (2H, m), 8.65 (1H,br s), 10.50 (1H, s), 12.30 (1H, s); IR (solid) 3177, 1606, 1589, 1530,1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834, 813, 766,707, 691; MS 332.3(M+H)⁺.

Example 305[5-(3-Hydroxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-76)

A solution of(5-benzyloxypropyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-78) (200 mg, 0.46 mmol) in toluene (4 mL) and acetonitrile (8 mL)was stirred with trimethylsilyl iodide (0.64 ml, 4.6 mmol) at 55° C. for3 hours to afford an amber coloured solution. This mixture was dilutedwith ethyl acetate and aqueous sodium hydrogen carbonate. The resultinglayers were separated, the organic layer was dried over magnesiumsulphate and concentrated in vacuo. Purification by flash chromatography(SiO₂, methanol-dichloromethane gradient) affords a yellow oil (115 mg).Trituration with dichloromethane affords III-76 as an off-white soliddried at 75° C. under vacuum (83 mg, 52%): mp 164-165° C.; ¹H NMR (DMSO)δ 1.80-1.90 (2H, m), 2.70-2.80 (2H, m), 3.50-3.60 (2H, m), 4.59 (1H, s),6.80 (1H, s), 7.50-7.60 (4H, m), 7.82-7.90 (2H, m), 8.48-8.53 (2H, m),8.63 (1H, s), 10.40 (1H, s), 12.25 (1H, s); IR (solid) 1622, 1587, 1574,1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952,833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H)⁺.

Example 306[5-(3-Methoxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-77)

mp 169-170° C.; ¹H NMR (DMSO-d6) δ 1.86-1.97 (2H, m), 2.75 (2H, t), 3.30(3H, s), 3.45 (2H, t), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H,m), 8.45-8.55 (2H, m), 8.67 (1H, d), 10.30 (1H, s), 12.25 (1H, s); IR(solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117,1003, 831, 764, 714, 695; MS 360.3(M+H)⁺.

Example 307[5-(3-Benzyloxyprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-78)

mp 177-178° C.; ¹H NMR (DMSO) δ 1.92-2.03 (2H, m), 3.76-3.85 (2H, m),3.52-3.62 (2H, m), 4.51 (2H, s), 6.82 (1H, s), 7.28-7.40 (5H, m),7.46-7.58 (4H, m), 7.80-7.85 (2H, m), 8.47-8.52 (2H, m), 8.66 (1H, d),10.45 (1H, s); IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426,1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H)⁺.

Example 308[5-(3-Aminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-79)

A solution of[5-(3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-80) (250 mg, 0.56 mmol), in dichloromethane (3 mL) at 0° C. wastreated with TFA (2 mL). The mixture was warmed to room temperature thenconcentrated in vacuo. The residue was triturated and concentrated fromdichloromethane (3×5 mL) and ether, then triturated with dichloromethaneto crystallize the TFA salt. The resulting solid was collected byfiltration and dissolved in a mixture of ethanol (3 mL) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then themixture allowed to crystallize. The product was collected by filtrationand dried at 80° C. under vacuum to afford III-79 as an off-white powder(122 mg, 63%): mp 205-207° C.; ¹H NMR (DMSO) δ 1.68-1.83 (2H, m),2.65-2.80(4H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H, m),8.45-8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid) 1621,1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776,764, 705, 677; MS 345.3(M+H)⁺.

Example 309[5-(3-tert-Butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-80)

mp 199-200° C.; ¹H NMR (DMSO) δ 1.37 (9H, s), 1.71-1.82 (2H,m), 2.67(2H, t), 3.00-3.11 (2H, m), 7.81 (1H, s), 7.99 (1H, s), 7.50-7.60 (4H,m), 7.80-7.85 (2H, m), 8.48-8.52 (2H, m), 8.63 (1H, d), 10.40 (1H, s),12.26 (1H, m); IR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481,1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848,807, 768, 740, 728, 710,693; MS 445.3 (M+H)⁺.

Example 3105-Isopropylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-81)

¹H NMR (500 MHz, DMSO-d6) δ 1.20 (d, J=6.6 Hz, 6H), 4.13 (m, 1H), 7.42(br. s, 1H), 7.61 (dd, J=7.0, 7.7 Hz, 2H), 7.66 (t, J=7.1 Hz, 1H), 7.71(m, 1H), 7.99 (m, 2H), 8.39 (m, 1H), 8.42 (d, J=7.1 Hz, 2H), 8.74 (d,J=8.2 Hz, 1H), 11.41 (br. s, 1H); EI-MS 373.2 (M+H); HPLC-Method C,R_(t) 14.09 min.

Example 311(5-Allylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-82)

¹H NMR (500 MHz, DMSO-d6) δ 4.02 (m, 2H), 5.15 (m, 1H), 5.23 (m, 1H),5.94 (m, 1H), 7.45 (br. s, 1H), 7.60 (t, J=6.9 Hz, 2H), 7.64 (m, 1H),7.72 (m, 1H), 7.98 (m, 2H), 8.43 (m 2H), 8.72 (d, J=8.2 Hz, 1H), 8.84(br. s, 1H), 11.34 (br. s, 1H); EI-MS 371.2 (M+H); HPLC-Method C, R_(t)13.67 min.

Example 312[5-(2-Methoxyethylcarbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-83)

¹H NMR (500 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.48 (m, 4H), 7.36 (br. s,1H), 7.62 (m, 2H), 7.63 (m, 1H), 7.71 (m, 1H), 7.98 (m, 2H), 8.41 (dd,J=1.4, 7.0, 2H), 8.70 (m, 2H), 11.30 (br. s, 1H); EI-MS 389.2 (M+H);HPLC-Method C, R_(t) 12.37 min.

Example 313(5-Benzylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-84)

¹H NMR (500 MHz, DMSO-d6) δ 4.52 (d, J=6.0 Hz, 2H), 7.29 (m, 1H), 7.38(d, J=4.2 Hz, 4H), 7.58 (t, J=7.5 Hz, 2H), 7.63 (m, 1H), 7.72 (m, 1H),7.98 (m, 2H), 8.43 (d, J=7.7 Hz, 2H), 8.72 (d, J=7.5 Hz, 1H), 9.23 (br.s, 2H), 11.34 (br. s, 1H); EI-MS 421.2 (M+H); HPLC-Method C, R_(t) 16.76min.

Example 314(5-Cyclohexylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-85)

¹H NMR (500 MHz, DMSO-d6) δ 1.16 (m, 1H), 1.34 (m, 4H), 1.62 (d, J=2.6Hz, 1H), 1.76 (m, 2H), 1.85 (m, 2H), 3.79 (m, 1H), 7.43 (m, 1H), 7.60(t, J=7.2 Hz, 2H), 7.65 (t, J=7.1 Hz, 1H), 7.71 (ddd, J=2.2, 5.4, 8.2Hz, 1H), 7.98 (m, 2H), 8.35 (m, 1H), 8.43 (dd, J=1.4, 7.2 Hz, 2H), 8.72(d, J=8.2 Hz, 1H), 11.34 (br. s, 1H); EI-MS 413.5 (M+H); HPLC-Method C,R_(t) 17.18 min.

Example 315(5-Diethylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-86)

¹H NMR (500 MHz, DMSO-d6) δ 1.18 (br. s, 3H), 1.25 (br. s, 3H), 3.49(br. s, 2H), 3.69 (b. s, 2H), 7.21 (s, 1H), 7.59 (t, J=6.9 Hz, 2H), 7.62(m, 1H), 7.70 (m, 1H), 7.96 (m, 2H), 8.39 (d, J=7.1 Hz, 2H), 8.74 (d,J=8.4 Hz, 1H), 11.37 (br. s, 1H); EI-MS 387.2 (M+H); HPLC-Method C,R_(t) 14.50 min.

Example 316[5-(Benzyl-methyl-carbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-87)

¹H NMR (500 MHz, DMSO-d6) δ 3.33 (s, 3H), 4.75 (s, 2H), 7.26 (m, 1H),7.31 (m, 1H), 7.38 (m, 4H), 7.58 (m, 2H), 7.70 (m, 1H), 7.95 (m, 3H),8.26 (m, 1H), 8.40 (d, J=7.8 Hz, 2H), 8.75 (m, 1H), 11.2 (br. s, 1H);EI-MS 435.2 (M+H); HPLC-Method C, R_(t) 16.77 min.

Example 317(2-Phenyl-quinazolin-4-yl)-(5-propylcarbamoyl-2H-pyrazol-3-yl)-amine(III-88)

¹H NMR (500 MHz, DMSO-d6) δ 0.94 (t, J=7.3 Hz, 3H), 1.57 (m, 2H), 3.24(q, J=6.5 Hz, 2H),-7.39 (br. s, 1H), 7.60 (t, J=7.3 Hz, 2H), 7.64 (m,1H), 7.71 (br. t, J=6.5 Hz, 1H), 7.98 (m, 2H), 8.42 (d, J=7.2 Hz, 2H),8.61 (br. s, 1H), 8.72 (d, J=8.5 Hz, 1H), 11.34 (br. s, 1H); EI-MS 373.3(M+H); HPLC-Method C, R_(t) 13.51 min.

Example 318[5-(Ethyl-isopropyl-carbamoyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-89)

¹H NMR (500 MHz, DMSO-d6) δ 0.92 (t, J=7.4 Hz, 6H), 1.52 (m, 2H), 1.59(m, 1H), 3.79 (m, 2H), 7.53 (br. s, 1H), 7.57 (t, J=7.5 Hz, 2H), 7.65(t, J=7.2 Hz, 1H), 7.71 (m, 1H), 7.99 (m, 2H), 8.23 (br. d, J=8.8 Hz,1H), 8.46 (d, J=7.5 Hz, 2H), 8.74 (d, J=8.4 Hz, 1H), 11.34 (br. s, 1H);EI-MS 401.2 (M+H); HPLC-Method C, R_(t) 15.51 min.

Example 319(5-Cyclopropylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-90)

¹H NMR (500 MHz, DMSO-d6) δ 0.60 (m, 2H), 0.74 (m, 2H), 2.86 (m, 1H),7.34 (br. s, 1H), 7.62 (m, 3H), 7.70 (m, 1H), 7.97 (m, 2H), 8.41 (d,J=7.9 Hz, 2H), 8.63 (br. s, 1H), 8.72 (d, J=7.8 Hz, 1H), 11.35 (br. s,1H); EI-MS 371.2 (M+H); HPLC-Method C, R_(t) 12.64 min.

Example 320(5-Isobutylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-91)

¹H NMR (500 MHz, DMSO-d6) δ 0.94 (d, J=6.7 Hz, 6H), 1.88 (m, 1H), 3.12(t, J=6.4 Hz, 2H), 7.45 (br. s, 1H), 7.58 (t, J=7.2 Hz, 3H), 7.64 (t,J=7.1 Hz, 1H), 7.71 (m, 1H), 7.98 (m, 2H), 8.44 (dd, J=1.3, 7.9 Hz, 2H),8.62 (br. s, 1H), 8.72 (d, J=8.3 Hz, 1H), 11.33 (br. s, 1H); EI-MS 387.2(M+H); HPLC-Method C, R_(t) 14.70 min.

Example 321{5-[(3S)-3-Methoxymethyl-pyrrolidine-1-carbonyl]-2H-pyrazol-3-yl}-(2-phenyl-quinazolin-4-yl)-amine(III-93)

¹H NMR (500 MHz, DMSO-d6) δ 2.00 (m, 2H), 2.12 (m, 1H), 3.29 (s, 3H),3.45 (t, J=8.7 Hz, 1H), 3.57 (dd, J=3.2, 9.3 Hz, 1H), 3.86 (m, 1H), 3.92(m, 1H), 4.36 (m, 2H), 7.45 (br. s, 1H), 7.59 (t, J=7.2 Hz, 2H), 7.63(m, 1H), 7.69 (m, 1H), 7.97 (m, 2H), 8.40 (d, J=7.5 Hz, 2H), 8.74 (d,J=7.6 Hz, 1H), 11.38 (br. s, 1H); EI-MS 429.2 (M+H); HPLC-Method C,R_(t) 13.84 min.

Example 322(2-Phenyl-quinazolin-4-yl)-(5-m-tolylcarbamoyl-2H-pyrazol-3-yl)-amine(III-94)

¹H NMR (500 MHz, DMSO-d6) δ 2.33 (S, 3H), 6.97 (d, J=7.5 Hz, 1H), 7.27(t, J=7.8 Hz, 1H), 7.62 (m, 7H), 7.72 (m, 1H), 7.98 (m, 2H), 8.46 (dd,J=2.0, 7.9 Hz, 2H), 8.71 (m, 1H), 10.29 (s, 1H), 11.31 (br. s, 1H);EI-MS 421.2 (M+H); HPLC-Method C, R_(t) 17.11 min.

Example 323(2-Phenyl-quinazolin-4-yl)-(5-p-tolylcarbamoyl-2H-pyrazol-3-yl)-amine(III-95)

¹H NMR (500 MHz, DMSO-d6) δ 2.30 (s, 3H), 7.20 (d, J=8.3 Hz, 2H), 7.62(m, 5H), 7.68 (d, J=8.3 Hz, 2H), 7.72 (m, 1H), 7.98 (m, 2H), 8.46 (dd,J=1.8, 7.0 Hz, 2H), 8.72 (m, 1H), 10.31 (s, 1H), 11.36 (br. s, 1H);EI-MS 421.2 (M+H); HPLC-Method C, R_(t) 16.95 min.

Example 324(5-Methylcarbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-96)

¹H NMR (500 MHz, DMSO-d6) δ 2.82 (d, J=4.6 Hz, 3H), 7.31 (br. s, 1H),7.62 (m, 3H), 7.69 (m, 1H), 7.97 (m, 2H), 8.42 (d, J=7.1 Hz, 2H), 8.59(br. s, 1H), 8.71 (d, J=8.0 Hz, 1H), 11.30 (br. s, 1H); EI-MS 345.1(M+H); HPLC-Method C, R_(t) 11.02 min.

Example 325[5-(Morpholine-4-carbonyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-97)

¹H NMR (500 MHz, DMSO-d6) δ 3.33 (m, 4H), 3.83 (m 4H), 7.34 (br. s, 1H),7.53 (m, 4H), 7.86 (m, 2H), 8.43 (m, 2H), 8.67 (d, J=8.6 Hz, 1H), 10.70(s, 1H), 13.56 (s, 1H); EI-MS 401.2 (M+H); HPLC-Method A, R_(t) 2.68min.

Example 326[5-(1-Methylpiperazine-4-carbonyl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-98)

¹H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 3H), 2.43 (m, 4H), 3.87 (m 4H),7.33 (br. s, 1H), 7.53 (m, 4H), 7.87 (m, 2H), 8.45 (m, 2H), 8.67 (d,J=7.6 Hz, 1H), 10.70 (s, 1H), 13.30 (s, 1H); EI-MS 414.2 (M+H);HPLC-Method A, R_(t) 2.38 min.

Example 327[5-(2-Hydroxyethylcarbamoyl-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-99)

¹H NMR (500 MHz, DMSO-d6) δ 3.36 (m, 2H), 3.52 (m, 2H), 4.79 (m, 1H),7.50 (m, 5H), 7.83 (m, 2H), 8.50 (m, 4H), 10.52 (br. s, 1H), 13.25 (s,1H); EI-MS 375.1 (M+H); HPLC-Method A, R_(t) 2.51 min.

Example 328(5-Carbamoyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (III-100)

To a solution of5-(2-phenyl-quinazolin-4-ylamino)-1H-pyrazole-3-carboxylic acid2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol) in DMF (20 ml) wasadded a solution of ammonia in 1,4-dioxane (0.5 M, 10 ml). The resultingmixture was stirred at room temperature for 24 h. After concentration ofthe solvents, the residue was added to water (20 ml). The resultingprecipitate was collected to afford III-100 (168 mg, 80%)as a yellowsolid. ¹H NMR (500 MHz, DMSO-d6) δ 7.77-7.51 (m, 6H), 7.86 (br s, 2H),8.11 (m, 1H), 8.50 (m, 2H), 8.63 (m, 1H), 10.52 (s, 1H), 11.25 (s, 1H);EI-MS 331.1 (M+H); HPLC-Method A, R_(t) 2.52 min.

Example 329 (4-Bromo-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-101)

Prepared according to Method A to afford a yellow solid, mp 189° C.; ¹HNMR (DMSO-d6) δ 7.44-7.46 (3H, m), 7.58 (1H, m), 7.87 (2H, d), 8.15 (1H,s), 8.31-8.34 (2H, m), 8.49 (1H, d), 10.08 (1H, s), 13.13 (1H, s); IR(solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H)⁺.

Example 330(4-Bromo-5-methyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-102)

mp 183-185° C.; ¹H NMR (DMSO) δ 2.33 (3H, br s), 7.44-7.46 (3H, m), 7.57(1H, m), 7.84-7.87 (2H, m), 8.31-8.34 (2H, m), 8.48 (1H, d), 10.05 (1H,s), 12.91 (1H, br s); IR (solid) 3362, 3065, 2831, 1619, 1578; MS380.2/382.2(M+H)⁺.

Example 331 (4-Cyano-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-103)

mp>250° C.; ¹H NMR (DMSO) δ 7.47-7.49 (3H, m), 7.64 (1H, m), 7.91 (2H,m), 8.40-8.43 (2H, m), 8.53 (1H, d), 8.71 (1H, d), 10.61 (1H, s), 13.60(1H, s); IR (solid) 3277, 3069, 2855, 2231, 1625; MS 313.2(M+H)⁺.

Example 332(5-Methyl-2H-pyrazol-3-yl)-(2-morpholin-4-yl-quinazolin-4-yl)-amine(III-104)

mp 223-224° C.; ¹H NMR (DMSO) δ 2.26(3H, s), 3.65(4H, m), 3.75(4H, m),6.44(1H, s), 7.12(1H, d), 7.33(1H, d), 7.56(1H, t), 8.37(1H, d),10.01(1H, s), 12.13(1H, br s); IR (solid) 1621, 1578, 1537, 1475, 1434,1385; MS 311.0 (M+H)⁺.

Example 333(5-Methyl-2H-pyrazol-3-yl)-(2-piperazin-1-yl-quinazolin-4-yl)-amine(III-105)

mp 179-181° C.; ¹H NMR (DMSO) δ 2.26(3H, s), 2.74 (4H, br s), 3.71(4H,br s), 6.43(1H, s), 7.08(1H, t), 7.30(1H, d), 7.53(1H, t), 8.34(1H, d),9.50(1H, s), 12.08(1H, br s); IR (solid) 2853, 1619, 1603, 1566, 1549,1539; MS 310.0 (M+H)⁺

Example 334[2-(4-Methylpiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-106)

mp 148-150° C.; ¹H NMR (DMSO) δ 1.06(3H, d), 1.03(2H, m), 1.51-1.70(3H,m), 2.26(3H, s), 2.86(2H, m), 4.73(2H, d), 6.44(1H, s), 7.06(1H, d),7.29(1H, d), 7.52(1H, t), 8.32(1H, d), 9.92(1H, s), 12.09(1H, br s); IR(solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS 323.0 (M+H)⁺.

Example 335[2-(4-Methylpiperazin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-107)

mp 105-107° C.; ¹H NMR (DMSO) δ 2.21(3H, s), 2.26(3H, s), 2.34(4H, m),3.75(4H, m), 6.45(1H, s), 7.09(1H, t), 7.31(1H, d), 7.54(1H, t),8.34(1H, d), 9.96(1H, s), 12.12(1H, br s); IR (solid) 2934, 2844, 2804,1620, 1593, 1572, 1536, 1476; MS 324.0 (M+H)⁺.

Example 336(5-Methyl-2H-pyrazol-3-yl)-(2-piperidin-1-yl-quinazolin-4-yl)-amine(III-108)

mp 294° C.; ¹H NMR (DMSO) δ 1.45-1.58 (4H, m), 1.63 (2H, m), 2.26 (3H,s), 3.79 (4H, m), 6.45 (1H, br s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H,t), 8.33 (1H, d), 9.92 (1H, s), 12.11 (1H, br s); IR (solid) 2929, 2847,1632, 1591, 1500, 1482, 1437, 1382; MS 309.3 (M+H)⁺.

Example 337(2-Azepan-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-109)

mp 269° C.; ¹H NMR (DMSO) δ 1.50 (4H, br s), 1.76 (4H, br s), 2.25 (3H,s), 3.78 (4H, t), 6.55 (1H, br s), 7.03 (1H, t), 7.28 (1H, d), 7.50 (1H,t), 8.33 (1H, d), 9.92 (1H, s), 12.09 (1H, br s); IR (solid) 3427, 2963,2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386,1427; MS 323.3 (M+H)⁺.

Example 338[2-(4-(2-Hydroxyethylpiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-110)

mp 175° C.; ¹H NMR (DMSO) δ 1.08 (2H, m), 1.38 (2H, m), 1.57-1.83 (3H,m), 2.26 (3H, s), 2.85 (2H, t), 3.47 (2H, m), 4.38 (1H, t), 4.75 (2H,d), 6.45 (1H, br s), 7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.32 (1H,d), 9.93 (1H, s), 12.12 (1H, br s); IR (solid) 3365, 3073, 2972, 2868,1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 (M+H)⁺.

Example 339(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-111)

To a solution of(5-cyclopropyl-1H-pyrazol-3-yl)-(2-chloro-quinazolin-4-yl)-amine (118mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine(0.49 mL, 4.1 mmol) and the reaction mixture heated at reflux overnight.The reaction mixture was concentrated in vacuo and the residue dissolvedin a mixture EtOH:water (1:3, 4 mL). Potassium carbonate (57 mg, 0.41mmol) was added and the mixture stirred at room temperature for 2 hours.The resulting suspension was filtered, washed with water (×2), andrinsed with Et₂O (×2) to afford III-111 as a white solid (123 mg, 85%):mp 190° C.; ¹H NMR (DMSO) δ 0.66 (2H, s), 0.93 (5H, br s), 1.07 (2H, d),1.66 (3H, s), 1.91 (1H, s), 2.85 (2H, t), 4.72 (2H, d), 6.33 (1H, s),7.06 (1H, t), 7.29 (1H, d), 7.52 (1H, t), 8.31 (1H, d), 9.95 (1H, s),12.18 (1H, br s); IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494,1481, 1453, 1435, 1394; MS 349.2 (M+H)⁺.

Example 340[2-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-112)

mp 191° C.; ¹H NMR (DMSO) δ 1.65 (4H, s), 2.26 (3H, s), 3.90 (4H, s),3.93 (4H, s), 6.43 (1H, br s), 7.09 (1H, t), 7.32 (1H, d), 7.54 (1H, t),8.35 (1H, d), 9.99 (1H, br s), 12.13 (1H, br s); IR (solid) 3069, 2964,2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3(M+H)⁺.

Example 341[2-(4-Cyclopentylamino-piperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-113)

mp 191° C.; ¹H NMR (DMSO) δ 1.33 (2H, d), 1.65 (4H, s), 1.87 (2H, d),2.20 (1H, s), 2.26 (3H, s), 2.49 (2H, s), 3.00 (2H, t), 3.36 (2H, s),4.61 (2H, d), 6.45 (1H, br s), 7.07 (1H, s), 7.31 (1H, d), 7.52 (1H, s),8.33 (1H, d), 9.94 (1H, br s), 12.12 (1H, br s); IR (solid) 3371, 2943,1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 (M+H)⁺.

Example 342[2-(4-Hydroxypiperidin-1-yl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(III-114)

mp 123° C.; ¹H NMR (DMSO) δ 1.34 (2H, d), 1.80 (2H, d), 2.26 (3H, s),3.24 (2H, t), 3.72 (1H, br s), 4.39 (2H, d), 4.70 (1H, d), 6.44 (1H, brs), 7.07 (1H, t), 7.30 (1H, d), 7.53 (1H, t), 8.33 (1H, d), 9.94 (1H, brs), 12.11 (1H, br s); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600,1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 (M+H)⁺.

Example 343(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-hydroxy-4-phenylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-115)

mp 131° C.; ¹H NMR (DMSO) δ 0.64 (2H, q), 0.93 (2H, q), 1.68 (2H, d),1.83-1.97 (3H, m), 3.20-3.45 (2H, m), 4.69 (2H, d), 5.11 (1H, s), 6.37(1H, br s), 7.08 (1H, t), 7.20 (1H, t), 7.31 (3H, t), 7.49 (2H, d), 7.53(1H, t), 8.33 (1H, d), 9.98 (1H, br s), 12.18 (1H, br s); IR (solid)3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481,1459, 1431, 1372, 1336, 1213, 994; MS 427.6 (M+H)⁺.

Example 344(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1,3-dihydro-isoindol-2-yl)-quinazolin-4-yl]-amine(III-116)

Prepared according to Method E-I to afford an off-white solid, mp 237°C.; ¹H NMR (DMSO-d6) δ 0.79 (2H, s), 1.00 (2H, d), 1.99 (1H, m), 4.92(4H, d), 6.72 (1H, br s), 7.13 (1H, t), 7.33 (2H, s), 7.30-7.48 (3H, m),7.58 (1H, t), 8.40 (1H, d), 10.12 (1H, s), 12.17 (1H, s); IR (solid)3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359,1141, 1027, 877, 814; MS 369.4 (M+H)⁺.

Example 345(2-Azepan-1-yl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(III-117)

mp 199-200° C.; ¹H NMR (DMSO-d6) δ 0.60-0.70 (2H, m), 0.90-1.00 (2H, m),1.45-1.57 (4H, m), 1.70-1.85 (4H, m), 1.88-1.97 (1H, m), 3.75-3.87 (4H,m), 6.42 (1H, s), 7.02 (1H, t), 7.27 (1H, d), 7.49 (1H, t), 8.29 (1H,d), 9.91 (1H, s), 12.19 (1H, br s); IR (solid) 2929, 1624, 1595, 1581,1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, 1000, 825, 754; MS349.2 (M+H)⁺.

Example 346(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinazolin-4-yl]-amine(III-118)

mp 182-184° C.; ¹H NMR (DMSO) δ 0.75 (2H, d), 1.02 (2H, d), 1.96 (1H,m), 2.89 (2H, m), 4.05 (2H, m), 4.94 (2H, s), 6.46 (1H, s), 7.10 (1H,t), 7.21 (4H, d), 7.37 (1H, d), 7.55 (1H, d), 8.36 (1H, d), 10.05 (1H,s), 12.23 (1H, br s); IR (solid) 1621, 1581, 1560, 1537, 1479, 1456,1426, 1396, 1374, 1341, 1222; MS 383.3 (M+H)⁺.

Example 347(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dihydro-indol-1-yl)-quinazolin-4-yl]-amine(III-119)

mp 150-153° C.; ¹H NMR (DMSO) δ 0.74 (2H, d), 0.98 (2H, d), 1.96 (1H,m), 3.15 (2H, t), 4.25 (2H, t), 6.45 (1H, br s), 6.88 (1H, t), 7.09 (1H,t), 7.20 (2H, m), 7.53 (1H, d), 7.65 (1H, t), 8.43 (2H, br s), 10.09(1H, s), 12.28 (1H, br s); IR (solid) 1621, 1588, 1577, 1564, 1537,1487, 1455, 1425, 1386, 1259; MS 369.3 (M+H)⁺.

Example 348(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-hydroxymethylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-120)

mp 142° C.; ¹H NMR (DMSO) δ 0.67 (2H, d), 0.96 (2H, d), 1.10 (2H, q),1.55-1.70 (3H, m), 1.91 (1H, m), 2.85 (2H, t), 3.28 (2H, s), 4.48 (1H,s), 4.76 (2H, d), 6.34 (1H, s), 7.06 (1H, t), 7.30 (1H, d), 7.52 (1H,t), 8.31 (1H, d), 9.96 (1H, s), 12.19 (1H, s); IR (solid) 3363, 3000,2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314,1241, 1186, 1091, 995, 941, 823; MS 365.8 (M+H)⁺.

Example 349(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dihydro-2H-quinolin-1-yl)-quinazolin-4-yl]-amine(III-121)

mp 137-145° C.; ¹H NMR (DMSO-d6) δ 0.55 (2H, d), 0.88 (2H, d), 1.78 (1H,m), 1.92 (2H, t), 2.75 (2H, t), 4.04 (2H, t), 6.20 (1H, br s), 6.97 (1H,t), 7.14 (1H, m), 7.19 (1H, t), 7.42 (1H, d), 7.61 (1H, t), 7.67 (1H,d), 8.43 (1H, d), 10.04 (1H, s), 12.21 (1H, br s); IR (solid) 1622,1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 (M+H)⁺.

Example 350(5-Methoxycarbonyl-2H-pyrazol-3-yl)-[2-(piperidine-1-yl)-quinazolin-4-yl]-amine(111-122)

¹H NMR (500 MHz, CDCl₃) δ1.7-1.8(6H,m), δ 3.8 (4H, m), δ 3.9 (3H, s), δ5.5 (1H, s), δ 7.15 (1H, t), δ 7.4 (1H, d), δ 7.6 (1H, t), δ 8.0 (1H,d). HPLC-Method B, (starting with 95% H₂O) R_(t) 7.4 min; MS (ES+)353.24 (M+H).

Example 351[5-(Piperidine-1-carbonyl)-2H-pyrazol-3-yl]-[2-(piperidine-1-yl)-quinazolin-4-yl]-amine(III-123)

HPLC-Method B, (starting with 95% H₂O:0.1% TFA) R_(t) 8.0 min; MS (ES+)406.30, (ES−) 404.30.

Example 352(5-Hydroxymethyl-2H-pyrazol-3-yl)-[2-(piperidin-1-yl)-quinazolin-4-yl]-amine(III-124)

To a solution of III-122 (10.0 mg, 0.028 mmol) in THF (6 mL) at ambienttemperature was slowly added a 1M solution of LiAlH₄ in THF (0.05 mL,0.05 mmol). After 15 minutes the solution was quenched with water and 1NHCl. The product was extracted from the aqueous layer with EtOAc. Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by preparatory HPLC to afford III-124 (4.0 mg,44%). HPLC-Method B, (starting with 95% H₂O:0.1% TFA) R_(t) 6.1 min; MS(ES+) 325.13 (M+H), (ES−) 323.13 (M−H).

Example 353(5-Carbamoyl-2H-pyrazol-3-yl)-[2-(piperidin-1-yl)-quinazolin-4-yl]-amine(III-125)

A solution of III-122 (1.5 g, 4.3 mmol) in 2.0 M NH₃/MeOH (100 mL) washeated at 110° C. for 2 days. The dark brown reaction mixture wasconcentrated in vacuo to afford a viscous oil which was purified bycolumn chromatography to yield 0.7 g (50%) of III-125. ¹H NMR (500 MHz,CD3OD-d₃) δ1.6 (4H,m), δ1.7 (2H,m), δ 3.3 (1H, s), δ 3.8 (4H, m), δ 5.5(1H, s), δ 7.15 (1H, t), δ 7.45 (1H, d), δ 7.55 (1H, t), δ 8.0 (1H, d);HPLC-Method B, (starting with 95% H₂O:0.1% TFA) R_(t) 5.9 min; MS (ES+)338.13, (ES−) 336.15.

Example 354(5-Carbamoyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-quinazolin-4-yl]-amine(III-126)

HPLC-Method B, (starting with 95% H₂O:0.1% TFA) R_(t) 6.4 min; MS (ES+)352.19, (ES−) 350.20.

Example 355(5,7-Difluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-amine(III-127)

¹H NMR (500 MHz, DMSO-d6) δ13.7 (s, 1H), 10.3 (s, br, 1H), 7.90 (d, 2H),7.52 (t, 1H), 7.45 (m, 3H), 7.26 (d, 1H), 2.99 (m, 2H), 2.75 (m, 2H),1.95 (br, 4H) ppm; MS (ES+) 378.24 (M+H); (ES−) 376.23 (M−H);HPLC-Method A, R_(t) 3.04 min.

Example 356(2-Phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-trifluoromethyl-1H-indazol-3-yl)-amine(III-128)

¹H NMR (500 MHz, DMSO-d6) δ13.4 (s, 1H), 10.2 (s, br, 1H), 8.13 (s, 1H),7.86 (d, 2H), 7.78 (d, 1H), 7.69 (d, 1H), 7.50 (t, 1H), 7.35 (dd, 2H),2.89 (m, 2H), 2.72 (m, 2H), 1.90 (s, br, 4H) ppm; MS (ES+) 410.24 (M+H);(ES−) 408.23 (M−H); HPLC-Method A, R_(t) 3.19 min.

Example 357 (7-Fluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-129)

¹H NMR (500 MHz, DMSO-d6) δ13.6 (s, 1H), 11.1 (s, br, 1H), 8.65 (d, 1H),8.03 (d, 2H), 7.95 (s, 2H), 7.67 (m, 1H), 7.45 (m, 2H), 7.33 (t, 2H),7.22 (dd, 1H), 6.99 (td, 1H) ppm. MS (ES+): m/e=356.20 (M+H);HPLC-Method A R_(t) 3.00 min.

Example 358 (5-Fluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-130)

¹H NMR (500 MHz, DMSO-d6) δ13.2 (s, 1H), 11.3 (s, br, 1H), 8.67 (d, 1H),8.04 (d, 2H), 7.96 (s, 2H), 7.70 (m, 1H), 7.58 (dd, 1H), 7.43 (m, 4H),7.28 (td, 1H) ppm. MS (ES+) 356.20 (M+H); HPLC-Method A, R_(t) 3.00 min.

Example 359(5,7-Difluoro-1H-indazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-131)

¹H NMR (500 MHz, DMSO-d6) δ13.7 (s, 1H), 8.65 (d, 1H), 8.04 (d, 2H),7.95 (s, 2H), 7.68 (m, 1H), 7.45 (m, 1H), 7.35 (m, 4H) ppm. MS (ES+):m/e=374.17 (M+H); HPLC-Method A, R_(t) 3.07 min.

Example 360(1H-Indazol-3-yl)-[2-(3-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine(III-132)

¹H NMR (500 MHz, DMSO-d6) δ 7.06 (t, 1H), 7.42 (t, 1H), 7.59 (d, 1H),7.63 (t, 1H), 7.66 (d, 1H), 7.71 (m, 1H), 7.80 (d, 1H), 7.98 (m, 2H),8.33 (s, 1H), 8.46 (d, 1H), 8.71 (d, 1H), 11.04 (br. s, 1H), 12.97 (s,1H); EI-MS 406.1 (M+1); HPLC-Method A, R_(t) 3.15 min.

Example 361(2-Phenyl-quinazolin-4-yl)-(1H-pyrazolo[4,3-b]pyridin-3-yl)-amine(III-133)

¹H NMR (500 MHz, DMSO-d6) δ13.3 (s, br, 1H), 11.4 (s, br, 1H), 8.78 (d,1H), 8.58 (dd, 1H), 8.24 (d, 1H), 8.10 (m, 2H), 7.95 (d, 2H), 7.86 (t,1H), 7.56 (m, 2H), 7.44 (t, 2H) ppm. MS (ES+) 339.11 (M+H); HPLC-MethodA, R_(t) 2.63 min.

Example 362[5-(3-Methoxy-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-134)

¹H NMR (500 MHz, MeOH-d4) δ8.65 (d, 1H), 8.17 (m, 3H), 8.10 (d, 1H),7.90 (t, 1H), 7.75 (t, 1H), 7.58 (m, 2H), 7.25 (t, 1H), 6.95 (m, 2H),6.85 (d, 1H), 6.80 (s, 1H), 3.64 (s, 3H) ppm. MS (ES+): m/e=462.2(M+H).

Example 363(6-Oxo-5-phenyl-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(III-135)

¹H NMR (500 MHz, MeOH-d4) δ8.61 (d, 1H), 8.13 (m, 3H), 8.05 (d, 1H),7.85 (t, 1H), 7.70 (t, 1H), 7.58 (m, 2H), 7.32 (m, 5H), 6.79 (s, 1H)ppm. MS (ES+): m/e=432.2(M+H).

Example 364[5-(4-Methoxy-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-136)

MS (ES+) 462.2(M+H).

Example 365[5-(2,4-Dichloro-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-137)

¹H NMR (500 MHz, MeOH-d4) δ8.63 (d, 1H), 8.17 (m, 4H), 7.89 (t, 1H),7.73 (t, 1H), 7.61 (t, 2H), 7.57 (d, 1H), 7.32 (m, 1H), 7.21 (d, 1H),6.84 (s, 1H) ppm. MS (ES+)

m/e=500.1(M+H).

Example 366[6-Oxo-5-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-138)

¹H NMR (500 MHz, MeOH-d4) δ8.55 (d, 1H), 8.19 (d, 2H), 7.92 (m, 2H),7.65 (m, 3H), 7.45 (t, 2H), 7.25 (t, 1H), 7.13 (t, 1H), 7.05 (t, 1H),6.75 (s, 1H) ppm. MS (ES+): m/e=500.2 (M+H).

Example 367[6-Oxo-5-(4-Phenoxy-phenyl)-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-139)

MS (ES+) 524.3(M+H).

Example 368[5-(4-Chloro-phenyl)-6-oxo-5,6-dihydro-1H-pyrazolo[4,3-c]pyridazin-3-yl]-(2-phenyl-quinazolin-4-yl)-amine(III-140)

MS (ES+) 466.2(M+H).

Example 369 (2-imidazol-1-yl-quinazolin-4-yl)-(1H-indazol-3-yl)-amine(III-141)

¹H NMR (500 MHz, DMSO-d6) δ 7.10 (t, 1H), 7.44 (t, 1H), 7.50 (br. s,1H), 7.60 (d, 1H), 7.72 (m, 2H), 7.77 (m, 1H), 7.88 (d, 1H), 7.98 (t,1H), 8.73 (d, 1H), 8.96 (s, 1H), 11.23 (s, 1H), 13.06 (s, 1H); EI-MS328.1 (M+1); HPLC-Method A, R_(t) 2.93 min.

Example 370(1H-Indazol-3-yl)-[2-(2-methyl-imidazol-1-yl-quinazolin-4-yl]-amine(III-142)

¹H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 7.10 (t, 1H), 7.43 (t, 1H),7.57 (d, 1H), 7.60 (d, 1H), 7.67 (d, 1H), 7.76 (td, 1H), 7.86 (d, 1H),7.91 (d, 1H), 8.01 (td, 1H), 8.72 (d, 1H), 11.15 (s, 1H), 13.10 (s, 1H);EI-MS 342.1 (M+1); HPLC-Method A, R_(t) 3.06 min.

Example 371 (1H-Indazol-3-yl)-(2-piperidin-1-yl-quinazolin-4-yl)-amine(III-143)

1H NMR (500 MHz, DMSO-d6) δ 1.48 (m, 6H), 3.60 (m, 4H), 7.11 (t, 1H),7.52 (t, 1H), 7.55 (d, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.75 (d, 1H),7.90 (t, 1H), 8.58 (d, 1H), 11.82 (br. s, 1H), 13.25 (s, 1H); EI-MS345.1 (M+1); HPLC-Method A, R_(t) 3.03 min.

Example 372(1H-Indazol-3-yl)-[2-(octahydro-quinolin-1-yl)-quinazolin-4-yl]-amine(III-144)

¹H NMR (500 MHz, DMSO-d6) δ 0.6-1.9 (m, 13 H), 3.15 (m, 1H), 3.25 (m,1H), 4.0 (m, 1H), 7.10 (t, 0.5H), 7.12 (t, 0.5H), 7.55 (m, 2H), 7.66 (d,0.5 H), 7.69 (d, 0.5 H), 7.77 (d, 1H), 7.91 (t, 1H), 8.55 (d, 0.5 H),8.59 (d, 0.5 H), 11.46 (s, 0.5 H), 11.54 (s, 0.5 H), 11.78 (s, 0.5 H),11.84 (s, 0.5 H), 13.10 (s, 0.5 H), 13.12 (s, 0.5 H); EI-MS 399.3 (M+1);HPLC-Method A, R_(t) 3.37 min.

Example 373(1H-Indazol-3-yl)-[2-(2,6-dimethyl-morpholin-4-yl)-quinazolin-4-yl]-amine(III-145)

¹H NMR (500 MHz, DMSO-d6) δ 1.0 (m, 6H), 4.0 (m, 6H), 7.12 (t, 1H), 7.41(td, 1H), 7.56 (t, 1H), 7.58 (d, 1H), 7.68 (dd, 1H), 7.77 (t, 1H), 7.93(t, 1H), 8.60 (d, 1H), 11.69 (s, 1H), 13.16 (s, 1H); EI-MS 375.3 (M+1);HPLC-Method A, R_(t) 2.93 min.

Example 374 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrimidin-4-yl)-amine(IV-1)

mp 245-246° C.; ¹H NMR (DMSO) δ 2.26 (3H, s), 6.32 (1H, br s), 7.07 (1H,br s), 7.48-7.54 (3H, m), 8.33-8.39 (3H, m), 9.87 (1H, s), 12.03 (1H,s); IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336;MS 252.2(M+H)⁺.

Example 375[6-(4-Acetamidophenylsulfanyl)-2-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-3)

A suspension of Fenclorim (4,6-dichloro-2-phenylpyrimidine)(0.1 g, 0.44mmol), 3-amino-5-methylpyrazole (0.045 g, 0.47 mmol),N,N-diisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067g, 0.44 mmol) in n-butanol (5 ml) were heated at 117° C. for 18 hours.The solvent was removed in vacuo and the crude product purified by flashchromatography (silica gel, 3:2 Petrol:EtOAc) to afford 0.037 g (29%yield) of(6-Chloro-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine as aoff-white solid. A suspension of the above pyrimidine (0.037 g, 0.13mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanolwas heated at 85° C. under nitrogen for 2 days. The reaction mixture wascooled to room temperature and the solvent removed in vacuo. Theconcentrate was dissolved in EtOAc, and washed with NaHCO₃ (sat, aq.).The organic layer is concentrated in vacuo, and the crude product bypreperative HPLC. The residual disulfide that still remained in themixture after HPLC may be removed by precipitation from EtOAc andfiltration. The mother liquor was concentrated to afford IV-3 (7 mg, 13%yield) as an off-white solid: mp 235-236° C.; ¹H NMR (DMSO) δ 2.10 (3H,s), 2.21 (3H, s), 6.33 (1H, br s), 7.50 (3H, m), 7.7-7.59 (2H, m),7.76-7.78 (2H, m), 8.25 (2H, m), 9.72, 10.26 and 11.93 (3 H, 3×br s); IR(solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174,1102, 1089, 1027, 1015, 984; MS 417.3 (M+H)⁺.

Example 376[2-(4-Methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-4)

mp 215-216° C.; ¹H NMR (CD₃OD) δ 0.96 (3H, d), 1.16 (2H, m), 1.66 (3H,m), 2.27 (3H, s), 2.86 (2H, t), 4.58 (2H, m), 4.78 (2H, exch.protons),6.13 (2H, m), 7.83 (1H, d); IR (solid) 1593, 1550, 1489, 1436, 1331,1246, 1231; MS 273.1 (M+H)⁺.

Example 377[2-(4-Methylpiperidin-1-yl)-5-nitropyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-5)

mp 185-187° C.; ¹H NMR (DMSO) δ 0.93 (3H, d), 1.06-1.18 (2H, m),1.68-1.80 (3H, m), 2.26 (3H, s), 3.01-3.12 (2H, m), 4.63 (1H, d), 4.80(1H, d), 6.39 (1H, s), 9.00 (1H, s), 10.41 (1H, s), 12.36 (1H, s); IR(solid) 1589, 1517, 1479, 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2(M+H)⁺.

Example 378[5-Amino-2-(4-Methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-6)

To a solution of IV-5 (48 mg, 0.151 mmol) in ethanol (2.0 mL) was addedtin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixtureheated at reflux for 3 hours. The reaction was cooled to roomtemperature and poured onto a mixture of 1MNaOH:dichloromethane:propanol (18:8:4 mL) and stirred for 15 minutes.The layers were separated and the aqueous layer extracted twice withdichloromethane. The combined organic layers were concentrated in vacuoand the residue purified by flash chromatography (silica gel, gradientdichloromethane:MeOH) to afford IV-6 as a grey solid (27 mg, 63%): ¹HNMR (DMSO) δ 0.88-1.04 (5H, m), 1.55-1.62 (3H, m), 2.21 (3H, s), 2.70(2H, m), 3.36 (2H, m), 4.40 (2H, m), 6.37 (1H, s), 7.49 (1H, s), 8.40(1H, s), 11.92 (1H, br s); MS 288.2 (M+H)⁺.

Example 379[5-Amino-6-methyl-2-(4-methylpiperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-7)

mp 172-175° C.; ¹H NMR (DMSO) δ 0.90 (3H, d), 1.03 (2H, m), 1.52-1.62(3H, m). 2.13 (3H, s), 2.20 (3H, s), 2.69 (2H, m), 3.92 (2H, br s), 4.44(2H, d), 6.35 (1H, s), 8.41 (1H, s), 11.85 (1H, br s); IR (solid) 1612,1589, 1489, 1446, 1317; MS 302.5 (M+H)⁺.

Example 380[6-Methyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IV-10): MS 342.34 (M+H); HPLC-Method E, R_(t) 1.334 min. Example 381[2-(4-Chloro-phenyl)-6-methyl-pyrimidin-4-yl]-(5-furan-2-yl-2H-pyrazol-3-yl)-amine(IV-11)

MS 352.11 (M+H); HPLC Method E, R_(t) 1.194 min.

Example 3825-Furan-2-yl-2H-pyrazol-3-yl)-(6-methyl-2-phenyl-pyrimidin-4-yl)-amine(IV-12)

MS 318.21 (M+H); HPLC-Method E, 1.192 min.

Example 383[6-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-phenyl-2-yl-2H-pyrazol-3-yl)-amine(IV-13)

MS 396.24 (M+H); HPLC-Method E, R_(t) 1.419 min.

Example 384(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(IV-14)

MS 386.08 (M+H); HPLC-Method E 1.347 min.

Example 385[2-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-6-methyl-pyrimidin-4-yl]-(5-furan-2-yl-2H-pyrazol-3-yl)-amine(IV-15)

MS 376.18 (M+H); HPLC-Method E, R_(t) 1.181 min.

Example 386[2-(2,3-Dihydro-bezo[1,4]dioxin-2-yl)-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-16)

MS 338.17 (M+H); HPLC-Method E, R_(t) 1.082 min.

Example 387(6-Ethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-17)

MS 280.18 (M+H); HPLC-Method E, R_(t) 1.024 min.

Example 388(6-Methyl-2-phenyl-pyrimidin-4-yl)-(5-phenyl-2H-pyrazol-3-yl)-amine(IV-19)

MS 328.51 (M+H); HPLC-Method E, R_(t) 1.192 min.

Example 389[6-Ethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-20)

MS 348.5 (M+H); HPLC-Method E, R_(t) 1.224 min.

Example 390(5-Furan-2-yl-2H-pyrazol-3-yl)-[6-methyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-amine(IV-21)

MS 332.23 (M+H); HPLC-Method E, R_(t) 1.139 min.

Example 391(6-Methoxymethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-22)

MS 296.31 (M+H); HPLC-Method E, R_(t) 0.971 min.

Example 392(5,6-Dimethyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-23)

MS 280.2 (M+H); HPLC-Method E, R_(t) 0.927 min.

Example 393(6-Methyl-2-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IV-24)

MS 266.18 (M+H); HPLC-Method E, R_(t) 0.925 min.

Example 394[6-Ethyl-2-(4-methyl-phenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-25)

MS 294.46 (M+H); HPLC-Method E, R_(t) 1.174 min.

Example 395[2-(4-Chloro-phenyl)-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-26)

MS 314.42 (M+H); HPLC-Method E R_(t) 1.213 min.

Example 396(5-Methyl-1H-pyrazol-3-yl)-(6-methyl-2-p-tolyl-pyrimidin-4-yl)-amine(IV-27)

MS 280.45 (M+H); HPLC-Method E, R_(t) 1.135 min.

Example 397(1H-Indazol-3-yl)-(6-methoxymethyl-2-phenyl-pyrimidin-4-yl)-amine(IV-28)

¹H NMR (500 MHz, DMSO) δ 3.57 (3H, s), 4.65 (2H, s), 7.23 (1H, J=7.5 Hz,t), 7.52 (1H, J=7.6 Hz, t), 7.63 (4H_(,) m), 7.75 (1H, br), 8.13 (1H,J=5.5 Hz, br d), 8.44 (1H, J=5.7 Hz, br d), 10.6 (1H, br), 12.8 (1H, brs) ppm; HPLC-Method A, R_(t) 2.944 min; MS (FIA) 332.1 (M+H)⁺.

Example 398(5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-yl)-amine(IV-29)

¹H NMR (DMSO) δ 2.34 (3H, s), 6.66 (1H, s), 7.53 (1H, d), 7.84 (1H, d),8.32 (2H, d), 8.70 (2H, d); MS 309.6 (M+H)⁺.

Example 399 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine (IV-30)

mp 225° C.; ¹H NMR (DMSO) δ 2.35 (3H, s), 6.81 (1H, s), 7.50-7.63 (3H,m), 8.45-8.52 (2H, m), 8.54 (1H, d), 8.62 (1H, d), 9.20 (1H, s), 10.79(1H, s), 12.38 (1H, br s); IR (solid) 2958, 2917, 2852, 1593, 1565,1524, 1467, 1450; MS 303.2 (M+H)⁺.

Example 400(5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[2,3-d]pyrimidin-4-yl)-amine(IV-31)

To a solution of 4-chloro-2-phenyl-pyrido[2,3-d]pyrimidine (J. Pharm.Belg., 29, 1974, 145-148) (109 mg, 0.45 mmol) in THF (15 mL) was added3-amino-S-methyl pyrazole (48 mg, 0.5 mmol) and the resulting mixtureheated at 65° C. overnight. The mixture was cooled to room temperatureand the resulting suspension was filtered and washed with Et₂O. Thesolid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7.The aqueous was extracted twice with ethyl acetate and the combinedorganic layers were dried (MgSO₄), filtered, and concentrated in vacuo.The residue was purified by flash chromatography (SiO₂, DCM-MeOHgradient) to afford IV-31 as an off-white solid (69 mg, 50%) mp 234° C.;1H NMR (DMSO) δ 2.14 (3H, s), 5.99 (1H, s), 7.20-7.40 (3H, m), 7.40-7.50(3H, m), 8.60 (1H, d), 8.79 (1H, d), 12.82 (1H, br s); IR (solid) 2957,2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H)⁺.

Example 401(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine(IV-32)

off-white solid, mp 232-233° C.; ¹H NMR (DMSO) δ 0.70-0.85 (2H, m),0.90-1.05 (2H, m), 1.05-2.07 (1H, m), 6.75 (1H, s), 7.50-7.75 (3H, m),8.40-8.70 (4H, m), 9.20 (1H, s), 10.80 (1H, s), 12.41 (1H); IR (solid)3178, 1601, 1573, 1532, 1484, 1452, 1409, 1367, 1328, 802, 781, 667; MS329.2 (M+H)⁺.

Example 402[2-(4-Methylpiperidin-1-yl)-purin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IV-33)

To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrousethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2mmol). The resulting mixture was stirred at room temperature for 48 h.The resulting precipitate was collected by filtration, washed withethanol, and dried under vacuum to afford 1.524 g (58% yield) of(2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine which was used inthe next step without further purification. To a solution of(2-chloro-purin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (200 mg, 0.80mmol) was added 4-methylpiperidine (4 mL, 8.01 mmol) and the reactionmixture heated at reflux overnight. The solvent was evaporated and theresidue dissolved in a mixture EtOH:water (1:3, 4 mL). Potassiumcarbonate (57 mg, 0.41 mmol) was added and the mixture was stirred atroom temperature for 2 hours. The resulting suspension was filtered,washed with water (×2) and rinsed with Et₂O (×2) to afford IV-33 as awhite solid (225 mg, 90%): mp >300° C.; H NMR (DMSO) δ 0.91 (3H, d),1.10 (2H, m), 1.65 (3H, m), 2.24 (3H, s), 2.84 (2H, m), 4.60 (2H, m),6.40 (1H, s) 7.87 (1H, m), 9.37-9.59 (1H, m), 12.03-12.39 (2H, m); IR(solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3(M+H)⁺.

Example 403(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methylpiperidin-1-yl)-pyrrolo[3,2-d]pyrimidin-4-yl]-amine(IV-34)

white solid; ¹H NMR (DMSO) δ 0.65 (2H, m), 0.91-0.96 (5H, m), 1.08 (2H,m), 1.58-1.64 (3H, m), 1.89 (1H, m), 2.77 (2H, t), 4.57 (2H, d), 6.09(1H, s), 6.38 (1H, s), 7.33 (1H, s), 9.42 (1H, s), 10.65 (1H, s), 12.02(1H, br s); MS 338.3 (M+H)⁺.

Example 404[6-Benzyl-2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)-amine(IV-35)

¹H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H), 10.4 (s, br, 1H), 9.73 (s, 1H,TFA-OH), 8.00 (d, 2H), 7.64 (m, 2H), 7.59 (dd, 1H), 7.52 (m, 3H), 7.41(t, 1H), 7.31 (m, 3H), 7.14 (dd, 1H), 4.58 (s, 2H), 4.35 (br, 2H), 3.74(m, 2H), 3.17 (s, 2H) ppm. MS (ES+): m/e=451.30 (M+H); HPLC-Method A,T_(ret) 2.96 min.

Example 405(5-Fluoro-1H-indazol-3-yl)-(2-phenyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-amine(IV-36)

Prepared from IV-35 (0.13 mmol) by treatment with an equal weight ofPd/C (10%) in 4.4% HCOOH in MeOH at room temperature for 12 h. Themixture was filtered through celite, the filtrate was evaporated, andcrude product was purified by HPLC to afford IV-36 as yellow solid in35% yield. ¹H NMR (500 MHz, DMSO-d6) δ 12.9 (s, 1H), 9.06 (s, 1H), 7.99(d, 2H), 7.57 (dd, 1H), 7.34 (m, 1H), 7.28 (m, 3H), 7.22 (d, 1H), 3.83(s, 2H), 3.05 (m, 2H), 2.72 (m, 2H) ppm. MS (ES+): m/e=361.20 (M+H);HPLC-Method A, T_(ret) 2.68 min.

Example 406 (5-Methyl-2H-pyrazol-3-yl)-(3-phenyl-isoquinolin-1-yl)-amine(V-1)

To a solution of 1-chloro-3-phenylisoquinoline (J. Het. Chem., 20, 1983,121-128)(0.33 g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added3-amino-5-methylpyrazole (0.27 g, 2.74 mmol) and potassium carbonate(0.57 g, 4.13 mmol)and the resulting mixture was heated at reflux for 6hours. The reaction mixture was then cooled and solvent removed invacuo. The residue was extracted twice with ethyl acetate and thecombined organic layers washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (SiO₂, gradient DCM-MeOH) to afford V-1 as a colourlessoil; ¹H NMR (MeOD) δ 2.23 (3H, s), 5.61 (1H, s), 7.41 (1H, m), 7.52(2H,m), 7.62(1H, m), 7.81(1H, m), 8.07(1H, d), 8.19(2H, m), 8.29(1H, s),8.54 (1H, d); MS 301.2 (M+H)⁺.

Example 407(1H-Indazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinoline-1-yl]-amine(V-2)

A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100mg, 0.326 mmol) and-1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol(3 mL) was heated at 160 C and the solvent evaporated with a stream ofnitrogen. The remaining oil was then heated at 160 C for 18 hours undernitrogen. The resulting melt was dissolved in 5%methanol:dichloromethane (50 mL), washed with saturated aqueous sodiumbicarbonate (1×25 mL) then dried over magnesium sulfate. Purification bysilica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2as a yellow solid (35 mg, 27%). ¹H NMR (500 MHz, d₆-DMSO) δ 9.78 (br s,1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.70-7.68 (m,1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.38(m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95-6.92 (m, 1H), 5.76 (s,1H); LC-MS (ES+) m/e=405.18 (M+H); HPLC-Method D R_(t) 2.74 min.

Example 408(5,7-Difluoro-1H-indazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine(V-3)

Prepared from 5,7-difluoro-1H-indazol-3-ylamineto afford compound V-3 asa yellow solid (90 mg, 63%). ¹H NMR (500 MHz, d₆-DMSO) δ 13.25 (s, 1H),9.92 (br s, 1H), 8.61 (d, 1H), 7.9 (d, 1H), 7.81-7.49 (m, 6H), 7.26-7.2(m, 2H), 7.12-7.10 (m, 1H); LC-MS (ES+) m/e=441.16 (M+H); HPLC-Method D,R_(t) 3.58 min.

Example 409 (5-Methyl-2H-pyrazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine(V-4)

To a mixture of 4-chloro-2-phenylquinoline (J. Het. Chem., 20, 1983,121-128)(0.53 g, 2.21 mmol) in diphenylether (5 mL) was added3-amino-5-methylpyrazole (0.43 g, 4.42 mmol) and the resulting mixtureheated at 200° C. overnight with stirring. The reaction mixture wascooled to ambient temperature then petroleum ether (20 mL) was added andthe resulting precipitate was isolated by filtration. The crude solidwas purified by flash chromatography (SiO₂, gradient DCM-MeOH) to affordV-4 as a white solid: mp 242-244° C.; ¹H NMR (DMSO) δ 2.27(3H, s),6.02(1H, s), 7.47(2H, d), 7.53-7.40(2H, br m), 7.67(1H, m), 7.92(1H, m),8.09(2H, d), 8.48(2H, m), 9.20(1H, s), 12.17(1H, br s); IR (solid) 1584,1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 (M+H)⁺.

Example 410 (1H-Indazol-3-yl)-(2-phenyl-quinolin-4-yl)-amine (V-5)

¹H NMR (500 MHz, d₆-DMSO) δ 12.78 (s, 1H), 9.50 (s, 1H), 8.65 (d, 1H),8.15 (s, 1H), 8.04-7.98 (m, 3H), 7.94 (s, 1H), 7.78-7.75 (m, 1H),7.60-7.40 (m, 6H), 7.15-7.10 (m, 1H). LC-MS (ES+) m/e=337.11 (M+H);HPLC-Method D, R_(t) 2.10 min.

Example 411(2-Phenyl-quinolin-4-yl)-(1H-pyrazolo[4,3-b]pyridin-3-yl)-amine (V-6)

¹H NMR (500 MHz, DMSO-d6) δ13.6 (s, 1H), 11.4 (s, 1H), 8.94 (d, 1H),8.61 (dd, 1H), 8.23 (d, 1H), 8.16 (dd, 1H), 8.12 (t, 1H), 7.89 (t, 1H),7.86 (d, 1H), 7.65 (m, 4H), 7.54 (s, 1H), 7.52 (dd, 1H) ppm. MS (ES+):m/e=338.11 (M+H); HPLC-Method A, HPLC-Method D, R_(t) 2.91 min.

Example 412(1H-Indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(V-7)

¹H NMR (500 MHz, d₆-DMSO) δ 12.68 (s, 1H), 9.51 (s, 1H), 8.7 (d, 1H),7.95-7.89 (m, 2H), 7.83-7.70 (m, 3H), 7.68-7.62 (m, 2H), 7.60 (s, 1H),7.55-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.12-7.09 (m,1H); LC-MS (ES+) m/e=405.15 (M+H); HPLC-Method D R_(t) 2.25 min.

Example 413(5,7-Difluoro-1H-indazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(V-8)

¹H NMR (500 MHz, d₆-DMSO) δ 13.31 (s, 1H), 9.49 (s, 1H), 8.70-8.67 (m,1H), 7.96-7.92 (m, 1H), 7.85-7.66 (m, 7H), 7.63-7.60 (m, 1H), 7.42-7.40(m, 1H). LC-MS (ES+) m/e=441.18 (M+H); HPLC-Method D R_(t) 2.39 min.

Example 414[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-(1H-pyrazolo[4,3-b]pyridin-3-yl)-amine(V-9)

¹H NMR (500 MHz, DMSO-d6) δ 13.6 (s, 1H), 11.6 (s, br, 1H), 8.98 (d,1H), 8.57 (dd, 1H), 8.12 (m, 3H), 7.97 (m, 2H), 7.86 (m, 3H), 7.49 (dd,1H), 7.23 (s, 1H) ppm. MS (ES+): m/e=406.20 (M+H); HPLC-Method A R_(t)2.91 min.

Example 415 (2-Phenyl-quinazolin-4-yl)-(2H-[1,2,4]triazol-3-yl)-amine(IX-154)

off-white solid, mp 266-267° C.; ¹H NMR (DMSO) δ 7.50-7.70 (4H, m),7.85-8.00 (2H, m), 8.15-8.25 (2H, m), 8.37-8.45 (2H, m), 8.58 (1H, d),13.90 (1H, br s); IR (solid) 3344, 3059, 1630, 1609, 1570, 1557, 1543,1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676,667, 654; MS 289.2 (M+H)⁺.

Example 416(5-Methyl-2H-[1,2,4]triazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine(IX-155)

¹H NMR (500 MHz, DMSO-d6) δ8.59 (s, 1H), 8.42 (d, J=6.7 Hz, 2H), 7.79(m, 4H), 8.03 (m, 2H), 7.74 (m, 4H), 2.51 (s, 3H) ppm. MS (ES+):m/e=303.08 (M+H); HPLC-Method A, R_(t) 2.64 min.

Example 417(2H-[1,2,4]-Triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(IX-47)

Pale yellow solid (52% yield). ¹H NMR (500 MHz, DMSO-d6) δ8.54 (s, 1H),8.15 (s, br, 1H), 7.91 (t, 1H), 7.85 (m, 2H), 7.76 (m, 3H), 7.66 (t, 1H)ppm. MS (ES+): m/e=357.13 (M+H); (ES−): m/e=355.15 (M−H); HPLC-Method A,R_(t) 2.81 min.

Example 418(5-Methyl-2H-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(IX-38)

Pale yellow solid (54% yield). ¹H NMR (500 MHz, DMSO-d6) δ8.44 (s, br,1H), 7.92 (m, 3H), 7.84 (m, 1H), 7.77 (m, 2H), 7.68 (t, 1H), 2.28 (s,3H) ppm. MS (ES+): m/e=371.14 (M+H); (ES−): m/e=369.18 (M−H);HPLC-Method A, R_(t) 2.89 min.

Example 419(5-Methylsulfanyl-2H-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethylphenyl)-quinazolin-4-yl]-amine(IX-156)

Pale yellow solid (65% yield). ¹H NMR (500 MHz, DMSO-d6) δ8.56 (br, 1H),7.90 (t, 1H), 7.84 (m, 2H), 7.78 (m, 2H), 7.67 (m, 2H), 2.51 (s, 3H,buried by DMSO) ppm. MS (ES+): m/e=403.12 (M+H); (ES−): m/e=401.16(M−H); HPLC-Method A, R_(t) 3.20 min.

Example 420(1H-[1,2,4]Triazol-3-yl)-[3-(2-trifluoromethyl-phenyl)-isoquinolin-1-yl]-amine(IX-175)

A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (0.326mmol) and 1H-[1,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) washeated at 160° C. and the solvent evaporated with a stream of nitrogen.The remaining oil was then heated at 160° C. for 18 hours undernitrogen. The resulting melt was dissolved in 5%methanol/dichloromethane (50 mL), washed with saturated aqueous sodiumbicarbonate (1×25 mL) then dried over magnesium sulfate. Purification bysilica gel chromatography afforded IX-175 as a colorless oil (4% yield).¹H NMR (500 MHz, CDCl₃) δ 9.18 (d, 1H), 8.82 (s, 1H), 7.90 (d, 1H),7.85-7.75 (m, 3H), 7.71-7.62 (m, 3H), 7.60-7.55 (m, 2H), 4.42-4.35 (m,1H). LC-MS (ES+) 356.16 (M+H); HPLC-Method D, R_(t) 3.55 min.

Example 421 (2-Phenyl-quinolin-4-yl)-(1H-[1,2,4]triazol-3-yl)-amine(IX-176)

Pale yellow solid (30% yield). ¹H NMR (500 MHz, d₆-DMSO) δ 13.82 (s,1H), 9.91 (s, 1H), 8.80 (s, 1H), 8.70-8.65 (m, 1H), 8.55 (s, 1H),8.15-8.12 (m, 2H), 8.03-7.98 (m, 1H), 7.75-7.72 (m, 1H), 7.57-7.49 (m,3H). LC-MS (ES+) m/e=288.11 (M+H); HPLC-Method D, R_(t) 1.55 min.

Example 422(1H-[1,2,4]triazol-3-yl)-[2-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine(IX-177)

Pale yellow solid (46% yield). ¹H NMR (500 MHz, d₆-DMSO) δ 13.70 (s,1H), 9.98 (s, 1H), 8.70 (d, 1H), 8.49 (s, 1H), 8.30 (s, 1H), 7.94-7.88(m, 2H), 7.80-7.68 (m, 3H), 7.64-7.56 (m, 2H). LC-MS (ES+) m/e=356.18(M+H); HPLC-Method D, R_(t) 1.68 min.

Example 423(1-H-Indazol-3-yl)-[5-methyl-6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine(II-251)

Colorless film; 2 H yield; ¹H-NMR (500 MHz, CD₃OD) δ 7.84 (m, 2H), 7.71(m, 3H), 7.41 (t, 2H), 7.14 (m, 1H), 3.74 (m, 4H), 3.69 (m, 4H), 1.24(s, 3H) ppm; HPLC-Method A R_(t) 3.26 min; MS (FIA) 455.1 (M+H).

Biological Testing

The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

Biological Testing Example 1 K_(i) Determination for the Inhibition ofGSK-3

Compounds were screened for their ability to inhibit GSK-3β (AA 1-420)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 μM to 30 μM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The K_(i) values were determined from the ratedata as a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 0.1 μMfor GSK-3: compounds II-1, II-105, II-33, II-34, II-36, II-39, II-38,II-39, II-40, II-41, II-42, II-46, II-57, II-59, II-60, II-61, II-62,II-63, II-64, II-66, II-67, II-69, II-70, II-53, II-71, II-99, II-73,II-74, II-75, II-76, II-77, II-7, II-8, II-9, II-10, II-24, II-19,II-78, II-54, II-79, II-80, II-81, II-82, II-83, II-84, II-56, II-86,II-20, II-25, II-26, II-85, II-21, II-27, II-28, II-87, II-88, II-29,II-11, II-12, II-30, II-31, II-13, II-14, II-15, II-16, II-17, II-18,II-79, II-23, II-2, II-90, II-91, II-92, II-93, II-3, II-4, II-5, II-6,II-94, II-95, II-96, II-107, II-108, II-109, II-110, II-124, II-125,II-111, II-112, II-113, II-114, II-115, II-116, II-117, II-118, II-119,II-120, II-121, II-208, III-8, III-7, III-9, III-37, III-38, III-39,III-40, III-42, III-45, III-46, III-47, III-48, III-49, III-51, III-52,III-53, III-54, III-55, III-56, III-57, III-58, III-59, III-60, III-61,III-62, III-63, III-30, III-65, III-66, III-67, III-70, III-73, III-31,III-75, III-76, III-77, III-33, III-34, III-106, III-108, III-109,III-111, III-35, III-116, III-117, III-118, III-119, III-120, III-121,III-127, III-128, III-141, III-130, III-131, IV-15, IV-16, IV-17, IV-20,IV-25, IV-26, IV-30, IV-34, V-3, and IX-47.

The following compounds were shown to have K_(i) values between 0.1 and1.0 μM for GSK-3: compounds II-103, II-104, II-35, II-44, II-45, II-49,II-50, II-97, II-101, II-22, II-32, III-41, III-43, III-44, III-28,III-50, III-29, III-64, III-71, III-74, III-78, III-82, III-88, III-90,III-102, III-105, III-107, III-110, III-112, III-114, III-115, III-122,III-124, III-124, IV-1, III-1, III-138, III-140, III-142, III-129,III-132, III-134, III-135, III-136, IV-1, IV-10, IV-11, IV-12, IV-13,IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV-6, IV-7, IV-8,IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V-7, IX-38, IX-154, and IX-177.

The following compounds were shown to have K_(i) values between 1.0 and20 μM for GSK-3: compounds II-43, II-65, II-48, II-47, II-51, II-68,II-52, II-72, II-100, II-98, II-89, III-68, III-81, III-83, III-91,III-94, III-95, III-96, III-97, III-98, III-99, III-100, III-101,III-103, III-123, III-137, III-139, III-143, III-145, III-146, V-4, V-8,IX-156, and IX-176.

Biological Testing Example 2 K_(i) Determination for the Inhibition ofAurora-2

Compounds were screened in the following manner for their ability toinhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration.

The following compounds were shown to have K_(i) values less than 0.1 μMfor Aurora-2: compounds II-33, II-34, II-36, II-37, II-40, II-41, II-55,III-7, III-9, III-37, III-38, III-39, III-40, III-41, III-42, III-44,III-45, III-46, III-47, III-48, III-49, III-50, III-51, III-52, III-53,III-54, III-55, III-56, III-57, III-59, III-60, III-61, III-63, III-30,III-65, III-66, III-67, III-70, III-31, III-76, III-77, III-78, III-80,III-32, III-33, III-34, III-106, III-108, III-109, III-110, III-111,III-112, III-114, III-35, III-115, III-116, III-117, III-118, III-119,III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

The following compounds were shown to have K_(i) values between 0.1 and1.0 μM for Aurora-2: compounds II-1, II-105, II-35, II-38, II-39, II-42,II-64, II-70, II-53, II-99, II-77, II-79, II-86, II-20, II-93, II-94,III-28, III-58, III-64, III-71, III-73, III-74, III-75, III-102,III-105, III-107, III-113, III-124, III-1, III-130, IV-1, IV-3, IV-4,IV-6, IV-29, IV-33, and V-4.

The following compounds were shown to have K_(i) values between 1.0 and20 μM for Aurora-2: compounds II-103, II-104, II-57, II-59, II-61,II-63, II-67, II-69, II-75, II-76, II-10, II-19, II-78, II-54, II-80,II-82, II-21, II-90, II-91, II-96, II-107, III-68, III-79, III-82,III-101, III-103, III-127, III-141, III-129, III-132,

IV-31, V-2, IX-47, IX-154, and IX-177.

Biological Testing Example 3 CDK-2 Inhibition Assay

Compounds were screened in the following manner for their ability toinhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mMMgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, Calif.)was added a DMSO solution of a compound of the present invention to afinal concentration of 30 μM. The resulting mixture was incubated at 30°C. for 10 min.

The reaction was initiated by the addition of 10 μL of CDK-2/Cyclin Astock solution to give a final concentration of 25 nM in the assay. Therates of reaction were obtained by monitoring absorbance at 340 nm overa 5-minute read time at 30° C. using a BioRad Ultramark plate reader(Hercules, Calif.). The K_(i) values were determined from the rate dataas a function of inhibitor concentration.

Biological Testing Example 4 ERK Inhibition Assay

Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%)for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

The following compounds were shown to have a K_(i) value of <1 μM forERK-2: III-109, III—III, III-115, III-117, III-118, III-120, and IV-4.

The following compounds were shown to have a K_(i) value of between 1 μMand 12 μM for ERK-2: III-63, III-40, and III-108.

Biological Testing Example 5 AKT Inhibition Assay

Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl, 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 pMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30° C. and 45 nM AKT. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

Biological Testing Example 6 SRC Inhibition Assay

The compounds were evaluated as inhibitors of human Src kinase usingeither a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay

The compounds were assayed as inhibitors of full length recombinanthuman Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressedand purified from baculo viral cells. Src kinase activity was monitoredby following the incorporation of 33P from ATP into the tyrosine of arandom poly Glu-Tyr polymer substrate of composition, Glu:Tyr=4:1(Sigma, cat. no. P-0275). The following were the final concentrations ofthe assay components: 0.05 M HEPES, pH 7.6, 10 mM MgCl₂, 2 mM DTT, 0.25mg/ml BSA, 10 μM ATP (1-2 μCi ³³P-ATP per reaction), 5 mg/ml polyGlu-Tyr, and 1-2 units of recombinant human Src kinase. In a typicalassay, all the reaction components with the exception of ATP werepre-mixed and aliquoted into assay plate wells. Inhibitors dissolved inDMSO were added to the wells to give a final DMSO concentration of 2.5%.The assay plate was incubated at 30° C. for 10 min before initiating thereaction with ³³P-ATP. After 20 min of reaction, the reactions werequenched with 150 μl of 10% trichloroacetic acid (TCA) containing 20 mMNa₃PO₄. The quenched samples were then transferred to a 96-well filterplate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310)installed on a filter plate vacuum manifold. Filter plates were washedfour times with 10% TCA containing 20 mM Na₃PO₄ and then 4 times withmethanol. 200 μl of scintillation fluid was then added to each well. Theplates were sealed and the amount of radioactivity associated with thefilters was quantified on a TopCount scintillation counter. Theradioactivity incorporated was plotted as a function of the inhibitorconcentration. The data was fitted to a competitive inhibition kineticsmodel to get the K_(i) for the compound.

Src Inhibition Assay B: Spectrophotometric Assay

The ADP produced from ATP by the human recombinant Src kinase-catalyzedphosphorylation of poly Glu-Tyr substrate was quanitified using acoupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In thisassay one molecule of NADH is oxidised to NAD for every molecule of ADPproduced in the kinase reaction. The disappearance of NADH can beconveniently followed at 340 nm.

The following were the final concentrations of the assay components:0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr,and 25 nM of recombinant human Src kinase. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,200 μM NADH, 30 pg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

In a typical assay, all the reaction components with the exception ofATP were pre-mixed and aliquoted into assay plate wells. Inhibitorsdissolved in DMSO were added to the wells to give a final DMSOconcentration of 2.5%. The assay plate was incubated at 30° C. for 10min before initiating the reaction with 100 μM ATP. The absorbancechange at 340 nm with time, the rate of the reaction, was monitored on amolecular devices plate reader. The data of rate as a function of theinhibitor concentration was fitted to competitive inhibition kineticsmodel to get the K_(i) for the compound.

The following compounds were shown to have a K_(i) value of <100 nM onSRC: III-31, III-32, III-33, III-34, III-35, III-47, III-65, III-66,III-37, III-38, III-39, III-40, III-42, III-44, III-48, III-49, III-70,III-45, III-78, III-76, and IV-32.

The following compounds were shown to have a K_(i) value of between 100nM and 1 μM for SRC: III-63, III-71, III-75, III-73, III-72, III-74,III-80, III-50, IV-30.

The following compounds were shown to have a K_(i) value of between 1 μMand 6 μM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of thisinvention, it is apparent that our basic construction can be altered toprovide other embodiments which utilize the compounds and methods ofthis invention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments which have been represented by way of example.

We claim:
 1. A compound of formula II:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;Ring C is a phenyl ring, wherein said Ring C has one or two orthosubstituents independently selected from —R¹, any substitutablenon-ortho carbon position on Ring C is independently substituted by —R⁵,and two adjacent substituents on Ring C are optionally taken togetherwith their intervening atoms to form a fused, unsaturated or partiallyunsaturated, 5-6 membered ring having 0-3 heteroatoms selected fromoxygen, sulfur or nitrogen, said fused ring being optionally substitutedby halo, oxo, or —R⁸; R¹ is selected from -halo, —CN, —NO₂, T—V—R⁶,phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, orC₁₋₆ aliphatic group, said phenyl, heteroaryl, and heterocyclyl ringseach optionally substituted by up to three groups independently selectedfrom halo, oxo, or —R⁸, said C₁₋₆ aliphatic group optionally substitutedwith halo, cyano, nitro, or oxygen, or R¹ and an adjacent substituenttaken together with their intervening atoms form said ring fused to RingC; R^(x) and R^(y) are independently selected from T—R³, or R^(x) andR^(y) are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ringheteroatoms selected from oxygen, sulfur, or nitrogen, wherein anysubstitutable carbon on said fused ring formed by R^(x) and R^(y) issubstituted by oxo or T—R³, and any substitutable nitrogen on said ringformed by R^(x) and R^(y) is substituted by R⁴; T is a valence bond or aC₁₋₄ alkylidene chain; R² and R² are independently selected from —R,—T—W—R⁶, or R² and R^(2′) are taken together with their interveningatoms to form a fused, 5-8 membered, unsaturated or partiallyunsaturated, ring having 0-3 ring heteroatoms selected from nitrogen,oxygen, or sulfur, wherein each substitutable carbon on said fused ringformed by R² and R^(2′) is substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and any substitutable nitrogen on said ring formed by R² andR^(2′) is substituted by R⁴; R³ is selected from —R, -halo, —OR,—C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR,—N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂; each R is independentlyselected from hydrogen or an optionally substituted group selected fromC₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, ora heterocyclyl ring having 5-10 ring atoms; each R⁴ is independentlyselected from —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆ aliphatic),—CON(R⁷)₂, or —SO₂R⁷, or two R⁴ on the same nitrogen are taken togetherto form a 5-8 membered heterocyclyl or heteroaryl ring; each R⁵ isindependently selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, or R⁵ and an adjacent substituent takentogether with their intervening atoms form said ring fused to Ring C; Vis —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—,—N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶), —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶), or —CON(R⁶)—; each R⁶ isindependently selected from hydrogen or an optionally substituted C₁₋₄aliphatic group, or two R⁶ groups on the same nitrogen atom are takentogether with the nitrogen atom to form a 5-6 membered heterocyclyl orheteroaryl ring; each R⁷ is independently selected from hydrogen or anoptionally substituted C₁₋₆ aliphatic group, or two R⁷ on the samenitrogen are taken together with the nitrogen to form a 5-8 memberedheterocyclyl or heteroaryl ring; and each R⁸ is independently selectedfrom an optionally substituted C₁₋₄ aliphatic group, —OR⁶, —SR⁶, —COR⁶,—SO₂R⁶, —N(R⁶)₂, —N(R⁶)N(R⁶)₂, —CN, —NO₂, —CON(R⁶)₂, or —CO₂R^(6.) 2.The compound according to claim 1, wherein said compound has one or morefeatures selected from the group consisting of: (a) Ring C is a phenylring, optionally substituted by —R⁵, wherein when Ring C and twoadjacent substituents thereon form a bicyclic ring system, the bicyclicring system is selected from an optionally substituted naphthyl,quinolinyl or isoquinolinyl ring; (b) R^(x) is hydrogen or C₁₋₄aliphatic and R^(y) is T—R³, or R^(x) and R^(y) are taken together withtheir intervening atoms to form an optionally substituted 5-7 memberedunsaturated or partially unsaturated ring having 0-2 ring nitrogens; (c)R¹ is -halo, an optionally substituted C₁₋₆ aliphatic group, phenyl,—COR⁶, —OR⁶, —CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶,—OC(O)NH₂, or —NHSO₂R⁶; and (d) R² is hydrogen and R² is hydrogen or asubstituted or unsubstituted group selected from aryl, heteroaryl, or aC₁₋₆ aliphatic group, or R² and R^(2′) are taken together with theirintervening atoms to form a substituted or unsubstituted benzo, pyrido,pyrimido or partially unsaturated 6-membered carbocyclo ring.
 3. Thecompound according to claim 2, wherein: (a) Ring C is a phenyl ring,optionally substituted by —R⁵, wherein when Ring C and two adjacentsubstituents thereon form a bicyclic ring system, the bicyclic ringsystem is selected from an optionally substituted naphthyl, quinolinylor isoquinolinyl ring; (b) R^(x) is hydrogen or C₁₋₄ aliphatic and R^(y)is T—R³, or R^(x) and R^(y) are taken together with their interveningatoms to form an optionally substituted 5-7 membered unsaturated orpartially unsaturated ring having 0-2 ring nitrogens; (c) R¹ is -halo,an optionally substituted C₁₋₆ aliphatic group, phenyl, —COR⁶, —OR⁶,—CN, —SO₂R⁶, —SO₂NH₂, —N(R⁶)₂, —CO₂R⁶, —CONH₂, —NHCOR⁶, —OC(O)NH₂, or—NHSO₂R⁶; and (d) R^(2′) is hydrogen and R² is hydrogen or a substitutedor unsubstituted group selected from aryl, heteroaryl, or a C₁₋₆aliphatic group, or R² and R^(2′) are taken together with theirintervening atoms to form a substituted or unsubstituted benzo, pyrido,pyrimido or partially unsaturated 6-membered carbocyclo ring.
 4. Thecompound according to claim 2, wherein said compound has one or morefeatures selected from the group consisting of: (a) Ring C is a phenylring, optionally substituted by —R⁵, wherein when Ring C and twoadjacent substituents thereon form a bicyclic ring system, the bicyclicring system is selected from an optionally substituted naphthyl ring;(b) R^(x) is hydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, orR^(x) and R^(y) are taken together with their intervening atoms to forma 5-7 membered unsaturated or partially unsaturated carbocyclo ringoptionally substituted with —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,; (c) R¹ is -halo, a C₁₋₆ haloaliphaticgroup, a C₁₋₆ aliphatic group, phenyl, or —CN; (d) R^(2′) is hydrogenand R² is hydrogen or a substituted or unsubstituted group selected fromaryl, or a C₁₋₆ aliphatic group, or R² and R^(2 ′) are taken togetherwith their intervening atoms to form a substituted or unsubstitutedbenzo, pyrido, pyrimido or partially unsaturated 6-membered carbocycloring; and (e) each R⁵ is independently selected from -halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R,—CO₂R, —CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R.
 5. The compoundaccording to claim 4, wherein: (a) Ring C is a phenyl ring, optionallysubstituted by —R⁵, wherein when Ring C and two adjacent substituentsthereon form a bicyclic ring system, the bicyclic ring system isselected from an optionally substituted naphthyl ring; (b) R^(x) ishydrogen or methyl and R^(y) is —R, N(R⁴)₂, or —OR, or R^(x) and R^(y)are taken together with their intervening atoms to form a 5-7 memberedunsaturated or partially unsaturated carbocyclo ring optionallysubstituted with —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN,—S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR,—N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁴)₂,; (c) R¹ is -halo, a C₁₋₆ haloaliphatic group, a C₁₋₆aliphatic group, phenyl, or —CN; (d) R^(2′) is hydrogen and R² ishydrogen or a substituted or unsubstituted group selected from aryl, ora C₁₋₆ aliphatic group, or R² and R^(2 ′) are taken together with theirintervening atoms to form a substituted or unsubstituted benzo, pyrido,pyrimido or partially unsaturated 6-membered carbocyclo ring; and (e)each R⁵ is independently selected from -halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —SO₂N(R⁴)₂, and —N(R⁴)SO₂R.
 6. The compoundaccording to claim 4, wherein said compound has one or more featuresselected from the group consisting of: (a) R^(x) is hydrogen or methyland R^(y) is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkyl- or an optionally substituted group selected from2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R^(x) and R^(y) aretaken together with their intervening atoms to form a 6-memberedunsaturated or partially unsaturated carbocyclo ring optionallysubstituted with -halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂wherein R is an optionally substituted C₁₋₆ aliphatic group; (b) R¹ is-halo, a C₁₋₄ aliphatic group optionally substituted with halogen, or—CN; (c) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and (d) each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).
 7. The compound according to claim 6, wherein: (a) R^(x) ishydrogen or methyl and R^(y) is methyl, methoxymethyl, ethyl,cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substitutedgroup selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, orR^(x) and R^(y) are taken together with their intervening atoms to forma benzo ring or a partially unsaturated carbocyclo ring optionallysubstituted with -halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, or —N(R⁴)₂wherein R is an optionally substituted C₁₋₆ aliphatic group; (b) R¹ is-halo, a C₁₋₄ aliphatic group optionally substituted with halogen, or—CN; (c) R² and R^(2′) are taken together with their intervening atomsto form a benzo, pyrido, pyrimido or partially unsaturated 6-memberedcarbocyclo ring optionally substituted with -halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, or —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group; and (d) each R⁵ is independentlyselected from —Cl, —F, —CN, —CF₃, —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄aliphatic)₂, —O(C₁₋₄ aliphatic), C₁₋₄ aliphatic, and —CO₂(C₁₋₄aliphatic).
 8. The compound according to claim 7, wherein R^(x) andR^(y) are each methyl or R^(x) and R^(y) are taken together with thepyrimidine ring to form an optionally substituted ring selected fromquinazoline or tetrahydroquinazoline, and R² and R^(2′) are takentogether with the pyrazole ring to form an optionally substitutedindazole ring.
 9. The compound according to claim 1, wherein saidcompound is selected from the following Table 1 compounds:


10. A composition comprising an effective amount of a compound accordingto claim 1, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 11. A method of inhibiting GSK-3 or Aurora activity in apatient comprising the step of administering to said patient atherapeutically effective amount of the composition according to claim10.
 12. The method according to claim 11, wherein said method inhibitsGSK-3 activity in a patient.
 13. A method of inhibiting GSK-3 or Auroraactivity in a biological sample comprising contacting said biologicalsample with the compound according to claim
 1. 14. A method of enhancingglycogen synthesis in a patient in need thereof, which method comprisesthe step of administering to said patient a therapeutically effectiveamount of the composition according to claim
 10. 15. A method oflowering blood levels of glucose in a patient in need thereof, whichmethod comprises the step of administering to said patient atherapeutically effective amount of the composition according to claim10.
 16. A method of inhibiting the production of hyperphosphorylated Tauprotein in a patient in need thereof, which method comprises the step ofadministering to said patient a therapeutically effective amount of thecomposition according to claim
 10. 17. A method of inhibiting thephosphorylation of β-catenin in a patient in need thereof, which methodcomprises the step of administering to said patient a therapeuticallyeffective amount of the composition according to claim
 10. 18. Thecomposition according to claim 10, further comprising an additionaltherapeutic agent selected from a treatment for Alzheimer's Disease, atreatment for Parkinson's Disease, an agent for treating MultipleSclerosis (MS), a treatment for asthma, an anti-inflammatory agent, animmunomodulatory or immunosuppressive agent, a neurotrophic factor, anagent for treating stroke, an agent for treating cardiovascular disease,or an agent for treating diabetes.
 19. The composition according toclaim 10, additionally comprising an anti-proliferative agent or achemotherapeutic agent.
 20. A method of treating cancer in a patient inneed thereof, comprising the step of administering to said patient atherapeutically effective amount of the composition according to claim10, wherein said cancer is melanoma or is selected from colon, lung,stomach, or breast cancer.
 21. The method according to claim 19,comprising the additional step of administering to said patient ananti-proliferative agent or a chemotherapeutic agent, wherein saidadditional therapeutic agent is administered together with saidcomposition as a single dosage form or separately from said compositionas part of a multiple dosage form.